AMYLOID-BINDING PEPTIDES, ANALOGUES AND USES THEREOF

The present invention relates to chemical compounds and compositions which comprise amyloid-binding peptide sequences, analogues and derivatives thereof, and methods and uses of the same for the diagnosis and treatment of diseases and disorders associated with a fundamental pathogenic process of protein or peptide misfolding and aggregation, called "amyloidosis".

1. BACKGROUND AND INTRODUCTION

1.1. Protein misfolding, aggregation and amyloidosis

A long and rapidly growing list of incurable degenerative ageing-related diseases and disorders has been linked to a generic and fundamental pathogenic process of protein or peptide misfolding and aggregation called

"amyloidosis". In each case, a specific protein or peptide aggregates in a specific part of the brain or body to form insoluble amyloid fibres, plaques or inclusions. These insoluble aggregates gradually accumulate in the affected tissues as the disease or disorder invariably develops over many years, so they are generally recognised as a strong, if not definitive indication of the disease or disorder in post-mortem analysis. Furthermore, they tend to form by a similar molecular mechanism (by the intermolecular association of β-strands into extended β-sheets), so they tend to share a similar molecular structure and a common ability to bind certain dyes such as Congo Red and Thioflavin T (Selkoe 2003; Stefani 2004).

These diseases and disorders, which are collectively referred to herein "amyloid-related diseases", fall into two main categories: those which affect the brain and other parts of the central nervous system; and those which affect other organs or tissues around the body, outside of the brain. Examples of amyloid-related diseases which fall under these two categories are listed below in the following two sections, however many other examples of rare hereditary amyloid-related diseases are known which are not included here and many more forms of amyloid-related disease are likely to be discovered in the future.

1.2. Neurodegenerative diseases associated with amyloidosis

Many different neurodegenerative diseases are associated with the misfolding and aggregation of a specific protein or peptide in a particular part of the brain, or elsewhere in the central nervous system, depending on the specific disease (Caughey and Lansbury 2003; Dev et al. 2003; Taylor et al. 2002; Wood et al. 2003; Masino 2004; Ross and Poirier 2004; Soto and Castilla 2004; Forman et al. 2004). For example:

Various forms of Alzheimer's disease (AD/FAD) as well as Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (HCHWA, Dutch type), cerebral amyloid angiopathy, and possibly also mild cognitive impairment and other forms of dementia are associated with the

aggregation of a 40/42-residue peptide called β-amyloid, Aβ(1-40) or Aβ(1- 42), which forms insoluble amyloid fibres and plaques in the cerebral cortex, hippocampus or elsewhere in the brain, depending on the specific disease; Alzheimer's disease is also associated with the formation of neurofibrillary tangles by aggregation of a hyperphosphorylated protein called tau, which also occurs in frontotemporal dementia (Pick's disease);

Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are associated with the aggregation of a protein called α-synuclein, which results in the formation of insoluble inclusions called "Lewy bodies";

Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease), dentatorubral pallidoluysian atrophy (DRPLA), different forms of spinocerebellar ataxia (SCA, types 1, 2, 3, 6 and 7), and possibly several other inheritable neurodegenerative diseases are associated with the aggregation of various proteins and peptides that contain abnormally expanded glutamine repeats (extended tracts of polyglutamine);

Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE) in cows, scrapie in sheep, kuru, Gerstmann-Straussler-Scheinker disease

(GSS), fatal familial insomnia, and possibly all other forms of transmissible encephalopathy are associated with the self-propagating misfolding and aggregation of prion proteins;

Amyotrophic lateral sclerosis (ALS), and possibly also some other forms of motor neuron disease (MND) are associated with the aggregation of a protein called superoxide dismutase;

Familial British dementia (FBD) and familial Danish dementia (FDD) are respectively associated with aggregation of the ABri and ADan peptide sequences derived from the BRI protein; and Hereditary cerebral hemorrhage with amyloidosis (HCHWA, Icelandic type) is associated with the aggregation of a protein called cystatin C.

1.3. Systemic diseases associated with amyloidosis

In addition to all those neurodegenerative diseases listed above, a wide variety of systemic ageing-related or degenerative diseases are associated with the misfolding and aggregation of a particular protein or peptide in various other tissues around the body, outside of the brain (Gejyo et al. 1985; Jaikaran and Clark 2001 ; Buxbaum 2004). For example:

Type Il diabetes (also known as adult-onset diabetes, or non-insulin dependent diabetes mellitus) is associated with the aggregation of a 37- residue peptide called the islet amyloid polypeptide (IAPP, or "amylin"), which forms insoluble deposits that are associated with the progressive destruction of insulin-producing β cells in the islets of Langerhans within the pancreas; Dialysis-related amyloidosis (DRA) and prostatic amyloid are associated with the aggregation of a protein called β ₂ -microglobulin, either in bones,

joints and tendons in DRA, which develops during prolonged periods of haemodialysis, or within the prostate in the case of prostatic amyloid;

Primary systemic amyloidosis, systemic AL amyloidosis and myeloma- associated amyloidosis are associated with the aggregation of immunoglobulin light chain (or in some cases immunoglobulin heavy chain) into insoluble amyloid deposits, which gradually accumulate in various major organs such as the liver, kidneys, heart and gastrointestinal (Gl) tract;

Reactive systemic AA amyloidosis, secondary systemic amyloidosis, familial Mediterranean fever and chronic inflammatory disease are associated with the aggregation of serum amyloid A protein, which forms insoluble amyloid deposits that accumulate in major organs such as the liver, kidneys and spleen;

Senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC) are associated with the misfolding and aggregation of different mutants of transthyretin protein (TTR), which form insoluble inclusions in various organs and tissues such as the heart (especially in FAC), peripheral nerves (especially in FAP) and gastrointestinal (Gl) tract; Another form of familial amyloid polyneuropathy (FAP, type II) is associated with the aggregation of apolipoprotein Al in the peripheral nerves;

Familial visceral amyloidosis and hereditary non-neuropathic systemic amyloidosis are associated with misfolding and aggregation of various mutants of lysozyme, which form insoluble deposits in major organs such as the liver, kidneys and spleen;

Finnish hereditary systemic amyloidosis is associated with aggregation of a protein called gelsolin in the eyes (particularly in the cornea);

Fibrinogen α-chain amyloidosis is associated with aggregation of the fibrinogen A α-chain, which forms insoluble amyloid deposits in various organs such as the liver and kidneys;

Insulin-related amyloidosis occurs by the aggregation of insulin at the site of injection in diabetics;

Medullary carcinoma of the thyroid is associated with the aggregation of calcitonin in surrounding tissues; Isolated atrial amyloidosis is associated with the aggregation of atrial natriuretic peptide (ANP) in the heart; and

Various forms of cataract are associated with the aggregation of γ-crystallin proteins in the lens of the eyes.

1.4. Pathogenic mechanism of amyloid-related diseases

While all these amyloid-related diseases share a common association with the pathogenic process of amyloidosis, the precise molecular mechanism by which this generic process of protein/peptide misfolding and aggregation is linked to the progressive degeneration of affected tissues is unclear. In some cases, including many of the systemic amyloid-related diseases, it is

thought that the sheer mass of insoluble protein or peptide simply overwhelms the affected tissues, ultimately leading to acute organ failure. In other cases, including most of the neurodegenerative diseases listed above, however, the symptoms of disease develop with the appearance of only very small aggregates and it was suggested that these insoluble deposits are inherently toxic and might cause the progressive destruction of cells in some way, for example by causing inflammation and oxidative stress, or by directly interfering with cell membranes or other cellular components or processes. In support of this, aggregated forms of the various proteins and peptides have been shown to be inherently toxic to cells in vitro. On the other hand, the specific sites of protein or peptide deposits do not always correspond precisely with the specific tissues which are destroyed in affected individuals and so it was suggested that these insoluble deposits may actually have a protective role. More recently, however, it has been established that the specific proteins and peptides involved in at least some of these amyloid-related diseases all form various soluble oligomeric species during their aggregation, which range in size from dimers and trimers, to much larger species comprising tens or even hundreds or thousands of protein or peptide monomers. Moreover, the oligomers are inherently toxic to cells in vitro in the absence of insoluble aggregates, and they appear to share a common structural feature as they can all be recognised by the same antibody despite the fact that they may be formed by proteins or peptides with very different amino acid sequences (Kayed et al. 2003; Glabe 2004; Walsh and Selkoe 2004). The molecular structure of these toxic soluble oligomers is not known and the precise mechanism by which they kill cells is also unclear, but several theories have been proposed. According to just one theory called the "channel hypothesis", for example, the oligomers form heterogeneous pores or leaky ion channels, which allow ions to flow freely through cell membranes, thereby destroying their integrity which ultimately causes cell death (Kagan et al.). Alternatively, or in addition, the oligomers may form protofibrils which kill cells by a similar or completely different mechanism.

Regardless of the precise pathogenic mechanism, however, an overwhelming amount of evidence has now been accumulated which suggests that the general process of protein/peptide aggregation is the primary cause of all these, and possibly other, different amyloid-related diseases.

1.5. Need for effective treatments and diagnostic agents Currently, there are no effective treatments for any of these amyloid-related diseases, which affect up to 100 million people in total throughout the developed world. All of the existing drugs help to treat some symptoms of these diseases for a limited period, but they quickly become ineffective as the progressive degeneration of tissues invariably continues to reduce quality of life and ultimately leads to acute organ failure. Alzheimer's disease costs the US economy alone almost $100 billion per year in direct costs and lost productivity, and the costs associated with diabetes are just as high. Therefore, unless more effective treatments are identified soon,

these diseases will lead to a global health crisis as their prevalence is expected to rise sharply with the ageing population.

Furthermore, there are no reliable diagnostic tests for any of these amyloid- related diseases, since definitive diagnosis can only be made by direct observation of insoluble amyloid deposits on post-mortem examination of the affected tissues, when it is clearly too late for therapeutic intervention. Consequently, there is a great need for reliable in vivo diagnostic agents that can be used to detect and monitor the build up of insoluble amyloid deposits during the earliest stages of these diseases in vivo, as soon as (or possibly even before) symptoms of the disease become apparent so that any available treatments can be provided in good time for maximum effect.

1.6. Overview of known amyloid-binding agents and inhibitors

A wide range of small organic amyloid-binding molecules have been identified, either as potential therapeutic agents or as potential diagnostic agents for imaging insoluble amyloid deposits in vivo. However, many of these are polycyclic and/or polyhydroxylated aromatic compounds, which tend to have poor solubility and target selectivity due to non-specific hydrophobic interactions, or small ionic compounds, which tend to have poor binding affinity, potency and bioavailability, as well as poor target selectivity due to their simple charged nature (De Lorenzi et al. 2004; Lansbury 2004; Bieler and Sot 2004; Kolstoe and Wood 2004; Citron 2004; LeVine 2004).

Moreover, while small organic molecules are generally well suited for tight and specific binding to more traditional drug targets such as the active sites of enzymes and the ligand-binding pockets of receptors and ion channels, their compact structures are not well suited for binding to the relatively flat molecular surfaces involved in protein-protein interactions. Consequently, they tend to suffer from low potency, poor target selectivity and flat, featureless structure-activity relationships which further limit their potential binding affinity and selectivity for the target protein or peptide (Walsh et al. 2003; LeVine 2002).

Alternatively, a number of peptide-based compounds have been reported to inhibit the aggregation of various target proteins and peptides into insoluble amyloid fibres. Invariably, these compounds are simple peptide fragments, derivatives or analogues which are essentially derived from or otherwise based on the natural amino acid sequence of the target amyloid-forming protein or peptide, or a particular section thereof. Moreover, either they consist of an unmodified fragment of the target protein or peptide, or some reversed, inversed, retro-in versed or scrambled version thereof, or they have been derived from such a peptide sequence, for example by making only a limited number of conservative amino acid substitutions, or by introducing various modifying groups into the peptide without substantially altering its amino acid sequence. For example, the following amino acid residues or other modifying groups have been incorporated into various peptide fragments derived from a natural amyloid-forming protein or peptide, or some reversed, inversed, retro-inversed or scrambled sequence thereof, in order to inhibit

aggregation of the native, unmodified full-length target protein or peptide by disrupting β-sheet formation:

(a) Proline residues (Soto et al. 1998; Poduslo et at. 1999; Soto 1999; Soto 1999; Adessi and Soto 2002; Bieler and Soto 2004); (b) Aminoisobutyric acid (Aib) residues (Formaggio et al. 2003; Gilead and Gazit 2004);

(c) N-methylated amino acid residues (Gordon et al. 2001 ; Doig et al. 2002; Gordon et al. 2002; Kapurniotu et al. 2002; Stott and Doig 2003; Cruz et al. 2004); and (d) Various N- or C-terminal modifying groups (Ghanta et al. 1996;

Findeis et al. 1999; Pallitto et al. 1999; Findeis and Molineaux 1999; Lowe et al. 2001; Findeis 2002).

However, the binding affinity and selectivity of these simple, naturally derived peptide analogues and derivatives is still limited and they suffer from a number of other disadvantages such as poor solubility, stability and/or bioavailability, which limits their potential utility as therapeutic and/or diagnostic agents in vivo.

It is therefore an aim of the present invention to provide chemical compounds and chemical compositions which can be used in the diagnosis and/or treatment of amyloid-related diseases which are associated with protein or peptide misfolding and aggregation.

2. SUMMARY OF THE INVENTION

It has been found that, to overcome the problems associated with known amyloid-binding agents and inhibitors, the most potent and selective amyloid-binding compounds are hydrophobic peptide fragments, analogues and derivatives which are not essentially derived from or otherwise based on any section of a target amyloid-forming protein or peptide, or which comprise a minimum number of amino acid residues that have a particular form of side chain (as described herein).

The present invention therefore provides:

A chemical compound, or a chemical composition comprising said chemical compound, wherein:

(a) the chemical compound comprises or consists of an amyloid-binding peptide sequence which binds to a target amyloid-forming protein or peptide;

(b) the amyloid-binding peptide sequence is selected from the group consisting of: i. a 5-residue amino acid sequence, X1-X2-X3-X4-X5; ϋ. a 4-residue amino acid sequence, X2-X3-X4-X5, wherein X1 is absent; and iii. a 3-residue amino acid sequence, X3-X4-X5, wherein both X1 and X2 are absent;

(c) X1 , X2, X3, X4 and X5 are consecutive amino acid residues which, when present, are linked together in sequence by optionally substituted amide groups to form a peptide backbone;

(d) each and every one of the amino acid residues in the amyloid-binding peptide sequence has a hydrophobic side chain comprising 2 or more carbon atoms including a β-carbon atom that is attached directly to an α-carbon atom in the peptide backbone by a single covalent bond; and

(e) the amyloid-binding peptide sequence possesses or comprises any 1 , 2, 3, 4 or more features selected from the group consisting of: i. the feature that the amyloid-binding peptide sequence is not essentially derived from or otherwise based on any section of the target amyloid-forming protein or peptide to which the amyloid-binding peptide sequence binds; ii. the feature that at least 2 amino acid residues in the amyloid- binding peptide sequence each have a hydrophobic side chain comprising 2 or 3 non-hydrogen atoms attached directly to a β- carbon atom by single covalent bonds, while no more than one residue in the amyloid-binding peptide sequence is a phenylalanine residue; iii. the feature that at least 1 amino acid residue in the amyloid- binding peptide sequence has a hydrophobic side chain comprising 2 or 3 non-hydrogen atoms attached directly to a β- carbon atom by single covalent bonds, and 5 or more carbon atoms in total; iv. the feature that at least 1 amino acid residue in the amyloid- binding peptide sequence has a hydrophobic side chain comprising 3 non-hydrogen atoms attached directly to a β- carbon atom by single covalent bonds; and v. the feature that at least 1 amino acid residue in the amyloid- binding peptide sequence has a hydrophobic side chain comprising a cyclic aliphatic ring which is connected directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond. A preferred emodiment of the present invention relates to a chemical compound comprising an amyloid-binding peptide sequence which binds to a target amyloid-forming protein or peptide wherein:

(a) the amyloid-binding peptide sequence is selected from the group consisting of: i. a 5-residue D-amino acid sequence, X1-X2-X3-X4-X5; ii. a 4-residue D-amino acid sequence, X2-X3-X4-X5, wherein X1 is absent; and iii. a 3-residue D-amino acid sequence, X3-X4-X5, wherein both X1 and X2 are absent;

(b) X1 , X2, X3, X4 and X5 are consecutive D-amino acid residues linked together in sequence by amide groups to form a peptide backbone wherein at least one of the D-amino acid residues within the peptide backbone is N-methylated or otherwise N-alkylated; (c) each of the amino acid residues in the amyloid-binding peptide sequence has a hydrophobic side chain; and

(d) at least 40% of the D-amino acid residues in the amyloid-binding peptide sequence have non-natural amino acid side chains.

The term "chemical compound" as used herein means any discrete chemical entity such as a molecule or salt, or any other form of chemical compound which has a defined chemical formula or molecular structure that may be represented on paper, for example. A "chemical composition" is any mixture or other physical or chemical combination of two, three, four or more chemical compounds, in any form. A "peptide sequence" means any specific peptide or section of peptide, or any defined sequence of amino acids within a peptide or section of peptide. In this sense, an "amyloid-binding peptide sequence" refers to any peptide sequence which, in the context of the chemical compound or composition as a whole, binds to, or otherwise associates with a target amyloid-forming protein or peptide. An "amyloid-forming protein or peptide" is any discrete protein or peptide molecule (distinct from the chemical compound or composition), which misfolds or otherwise aggregates to form soluble oligomers, protofibrils, ion channels, insoluble amyloid fibres, plaques or inclusions, or any other misfolded or aggregated form of the protein or peptide. Moreover, a "target amyloid-forming protein or peptide" is herein defined as any amyloid forming protein or peptide to which an amyloid- binding peptide sequence of the present invention binds. Examples of target amyloid-binding proteins and peptides are provided in later sections.

As used herein, the term "consists of or "consisting of shall be interpreted as meaning "is composed substantially of, where all of the key features or components which are included are specifically listed or described; while the term "comprises" or "comprising" shall be interpreted as meaning "contains" or "containing", "includes" or "including" (as the context permits), where only one, some, or potentially all of the key features or components are specifically disclosed. Thus, the chemical compounds of the present invention are either composed substantially of an amyloid binding-peptide sequence, or else they contain or include an amyloid-binding peptide sequence in addition to one or more additional key features or components which are not necessarily disclosed herein. The amyloid-binding peptide sequence may have N- and/or C- terminal modifications. When a chemical compound of the present invention "consists of or is "consisting of an amyloid-binding peptide sequence, having a distinct number of amino acid residues, the term "consists of or ' "consisting of does not exclude the presence of N- and/or C- terminal modifications, as identified in the present application. The N- and/or C- terminal modifications form part of the terminal amino acid residue.

Where a range of values of a particular feature are referred to by the terms "at least", "or more" or "more than" they are intended to signifiy that a higher number or value of the feature in question is preferred or that that the number or value tends towards the top end of a range. Furthermore, where a range of values of a particular feature are referred to by the terms "no more than", "at most" or "less/fewer than" they are intended to show that a lower number or value of the relevant feature is preferred or that the number or value tends towards the bottom end of a range.

A "peptide" or "section of a peptide" consists of a specific sequence of amino acid residues which are linked together by amide bonds to form a peptide backbone; and an "amino acid residue" is an amino acid which has been incorporated into a peptide or section of peptide. Amino acids consist of an amino group and a carboxyl group, which are connected by one or more carbon atoms, and a side chain consisting of a hydrogen atom or a larger chemical group, which is attached directly to one carbon atom between those amino and carboxyl groups. For example, α-amino acids have the general form H ₂ N-CH(R)-CO ₂ H wherein an α-amino group (H ₂ N) is connected to the α-carboxyl group (CO ₂ H) by a single carbon atom (the α-carbon atom), to which the side chain (R) is directly attached; and the corresponding α-amino acid residues within a peptide sequence have the general form NH-CH(R)-CO. Successive amino acid residues in a peptide sequence are linked by amide (CONH) groups formed by the carbonyl (CO) group of each amino acid residue and the NH group of the next amino acid residue in the peptide sequence. Naturally occurring proteins and peptides tend to be composed entirely of α-L-amino acid residues, wherein the asymmetric α-carbon atom has the S(+) stereochemical configuration, whereas the α-carbon atom in α-D- amino acid residues has the reverse R(-) stereochemical configuration. It will be appreciated by the person skilled in the art, that the amyloid-binding peptide sequences of the present invention include any form of amino acid residue as described herein.

When used in relation to the present invention, the term "natural amino acid side chain" means any side chain found in any of the naturally occurring amino acids selected from the list comprising: Alanine (Ala), Asparagine (Asp), Cysteine (Cys), Glutamine (GIn), lsoleucine (He), Leucine (Leu),

Methionine (Met), Phenylalanine (Phe), Proline (Pro), Serine (Ser), Threonine (Thr), Tryptophan (Trp), Tyrosine (Tyr), Valine (VaI), Aspartic Acid (Asp), Glutmain Acid (GIu), Arginine (Arg), Histidine (His) and Lysine (Lys). Although not themselves naturally occurring, the D-enantiomers of the aforementioned amino acids are considered to have "natural amino acid side chains".

A "non-natural amino acid side chain" is any side chain not found in the naturally occurring amino acids discussed above. Glycine (GIy) is not included in the above list because no side chains are attached to the α-carbon atom.

The reference to N-substituted (and more specifically N-methylated or N- alkylated) amino acid residues within the peptide backbone, relates to the

substitution of the N-σ atom that forms part of the amide (CONH) group linking successive amino acid residues in an amyloid-binding peptide sequence. The location of substitutued N-α atoms within an amyloid- binding peptide sequence may be identified as the N-σ atoms of specific amino acid residues; or as the N-σ atoms that form part of the amide

(CONH) group linking successive amino acid residues.

Where more than one amino acid residue within the peptide backbone of an amyloid-binding peptide sequence is N-substituted, the N-substituted residues are spaced such that they are separated by odd numbers of residues.

The term "N-terminal modifications" relates to substitution of one or more of the hydrogen atoms present on the free -NH ₂ terminal group. The term "C- terminal modifications of the amide group" relates to substitution of one or more of the hydrogen atoms present on the on the free -CONH ₂ terminal group.

Reference to N-substituted (and more specifically N-methylated or N- alkylated) amino acid residues within the peptide backbone does not include N-terminal modifications or C-terminal modifications of the amide group. The term "treatment", as used herein, may be used in relation to the curing or amelioration of a disease or disorder. Alternatively, it may cover any preventative or prophylactic treatment. Furthermore, the term "diagnonis" is intended to cover both the diagnosis and/or prognosis of a disease or disorder. When the term "subject" is used herein, it preferably means a mammalian, or more preferably a human subject.

The amyloid-binding peptide sequence of the present invention is a peptide sequence consisting of either 3, 4 or 5 consecutive amino acid residues. In particular, the amyloid-binding peptide sequence is selected from the group consisting of: i. a 5-residue amino acid sequence represented by the formula ii. X1-X2-X3-X4-X5; iii. a 4-residue amino acid sequence, X2-X3-X4-X5, wherein X1 is absent; and iv. a 3-residue amino acid sequence, X3-X4-X5, wherein both X1 and X2 are absent; wherein X1 , X2, X3, X4 and X5 are consecutive amino acid residues.

Those amino acid residues which are present in the amyloid-binding peptide sequence (as indicated above) are linked together in sequence by amide groups (or by substituted amide groups) to form a peptide backbone (or substituted peptide backbone), which includes the α-carbon atoms to which the side chain of each amino acid residue is directly attached. For the sake of clarity and succinctness, the term "peptide backbone" shall be interpreted as meaning either an unsubstituted peptide backbone wherein all the amino acid residues in the amyloid-binding peptide sequence are linked together by unsubstituted amide groups, or a substituted peptide backbone wherein any two or more amino acid residues in the amyloid-

binding peptide sequence are connected by substituted amide groups, or by amide group analogues (as the context allows or requires).

The present invention requires that each and every one of the amino acid residues in the amyloid-binding peptide sequence has a hydrophobic side chain comprising two or more carbon atoms, including one carbon atom

(the β-carbon atom) which is attached directly to the peptide backbone of the amyloid-binding peptide sequence (more specifically to the α-carbon atom of each amino acid residue, which forms part of the peptide backbone) by a single covalent bond. The term "hydrophobic" as used here in relation to an amino acid side chain or other group means "essentially or substantially hydrophobic in character" or otherwise "capable of forming a significant hydrophobic interaction". For guidance only, a hydrophobic side chain or group is one which is preferably at least as hydrophobic in overall character as any specific side chain or group disclosed herein. For further guidance a hydrophobic side chain or group is one which is at least as hydrophobic as a methoxymethyl group, and preferably more hydrophobic than an ethyl group. Hydrophobicity can be predicted by comparing logP values. Thus, hydrophilic amino acid residues such as alanine, serine and threonine are specifically excluded, unless they are modified to make them more hydrophobic.

2.3. Features of the invention

In embodiments of the invention the amyloid-binding peptide sequence possesses or comprises any one feature, or any combination of 2, 3, 4 or more features selected from the group consisting of: i. the amyloid-binding peptide sequence is not essentially derived from or otherwise based on any section of the target amyloid- forming protein or peptide to which the amyloid-binding peptide sequence binds; ii. at least 2 amino acid residues in the amyloid-binding peptide sequence each have a hydrophobic side chain comprising 2 or

3 non-hydrogen atoms attached directly to a β-carbon atom by single covalent bonds, while no more than one residue in the amyloid-binding peptide sequence is a phenylalanine residue; iii. at least 1 amino acid residue in the amyloid-binding peptide sequence has a hydrophobic side chain comprising 2 or 3 non- hydrogen atoms attached directly to a β-carbon atom by single covaient bonds, and 5 or more carbon atoms in total; iv. at least 1 amino acid residue in the amyloid-binding peptide sequence has a hydrophobic side chain comprising 3 non- hydrogen atoms attached directly to a β-carbon atom by single covalent bonds; and v. at least 1 amino acid residue in the amyloid-binding peptide sequence has a hydrophobic side chain comprising a cyclic aliphatic ring which is connected directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond.

The features listed immediately above are herein referred to as "alternative essential features", on the basis that the amyloid-binding peptide sequence possesses or comprises at least one of those features, but may possess or comprise any one of the following combinations thereof:

(i) Oi) ⁺ (V) (ii)+(ιii)+(v)

(ϋ) (Ui) ⁺ Ov) (ii)+(iv)+(v)

(iii) (Ui) ⁺ (V) (iii)+(iv)+(v)

(iv) Ov) ⁺ (V) (i)+(iι)+(iii)+(iv)

(V) O) ⁺ (U) ⁺ (Ui) (i)+(ii)+(iii)+(v)

(0+00 O) ⁺ OO ⁺ Ov) (i)+(ii)+(iv)+(v)

O) ⁺ (Ui) O) ⁺ Oi) ⁺ (V) (i)+(iii)+(iv)+(v)

O) ⁺ Ov) (i)+(iii)+(iv) (ii)+(iii)+(iv)+(v)

(i) ⁺ (v) O) ⁺ Ou) ⁺ (V) (i)+(iι)+(iιι)+(iv)+(v)

(U) ⁺ Ov) (ii)+(iii)+(iv)

Although it is likely that the compounds of the present invention will possess or comprise at least one of the aforementioned alternative essential features, these features may exist inherently as a result of other features present in the compounds.

2.3(i), First alternative essential feature of the invention.

Regarding the first alternative essential feature of the present invention (see i above), the amyloid-binding peptide sequence is not essentially derived from or otherwise based on any section of the target amyloid- forming protein or peptide to which the amyloid-binding peptide sequence binds. This means that the specific sequence of amino acid side chains in the amyloid-binding peptide is not substantially similar to any section of the target amyloid-forming protein or peptide to which the amyloid-binding peptide sequence binds (the "target amino acid sequence") or to any reversed, inversed, retro-inversed or scrambled sequence thereof. A reversed peptide sequence consists of the same sequence of amino acid residues, but in reverse order; and an inversed peptide sequence consists of the same sequence of amino acid residues, but each amino acid residue has the opposite stereochemistry to the corresponding amino acid residue in the original peptide sequence, so that the entire peptide sequence is the mirror image of the original. A retro-inversed peptide sequence is a reversed peptide sequence in which each amino acid residue has the opposite stereochemistry; while in a scrambled peptide sequence, the same amino acid residues are present, but in any order. For example, in the case of an amyloid-binding peptide sequence which binds to the target amino acid sequence [(L-Leu)-(L-Val)-(L-Phe)-(L-Phe)-(L-Ala)] that forms part of the amyloid-forming β-amyloid peptide associated with Alzheimer's disease, the amyloid-binding peptide sequence is not substantially similar

to this particular amino acid sequence, or to any of the following peptide sequences based thereon: [(L-Ala)-(L-Phe)-(L-Phe)-(L-Val)-(L-Leu)j (the reversed target peptide sequence); [(D-Leu)-(D-Val)-(D-Phe)-(D-Phe)-(D- AIa)] (inversed sequence); [(D-Ala)-(D-Phe)-(D-Phe)-(D-Val)-(D-Leu)] (retro-inversed target peptide sequence); or [(L-Phe)-(L-Ala)-(L-Leu)-(L-

Phe)-(L-Val)] Gust one example of a scrambled sequence). In particular, the amyloid-binding peptide sequence preferably differs from all of these peptide sequences by at least 1, preferably 2, more preferably 3, even more preferably 4, or ideally 5 amino acid side chains (depending on the length of the amyloid-binding peptide sequence). Alternatively, the amino acid side chains of the amyloid-binding peptide sequence may differ from all of these peptide sequences by at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

2.3(H). Second alternative essential feature of the invention.

Regarding the second alternative essential feature of the present invention (see ii above), at least 2 amino acid residues in the amyloid-binding peptide sequence each have a hydrophobic side chain comprising 2 or 3 non- hydrogen atoms attached directly to their β-carbon atoms by single covalent bonds, while no more than one amino acid residue in the amyloid-binding peptide sequence has a phenylmethyl side chain. A "non-hydrogen atom" means any atom which is not a hydrogen atom, for example a nitrogen atom, preferably an oxygen or sulphur atom, or more preferably a carbon atom. The β-carbon atom of each amino acid side chain is the carbon atom in the amino acid side chain which is attached directly to the peptide backbone of the amyloid-binding peptide sequence (more specifically to the α-carbon atom of the amino acid residue, which forms part of the peptide backbone) by a single covalent bond (see above). Therefore, according to this second alternative essential feature of the present invention, the side chains of at least two amino acid residues in the amyloid-binding peptide sequence each comprise a β-carbon, plus 2 or 3 carbon, nitrogen, oxygen, sulphur or other non-hydrogen atoms (excluding an α-carbon atom of the amino acid residue that forms part of the peptide backbone) which are attached directly to that β-carbon by single covalent bonds. By way of example, suitable amino acid residues that fall into this category include, but are not limited to:

VaI, He, allo-lle, Tie, 3-Peg, Tpg, Thr(O-alk), allo-Thr(O-alk), Pen(S- alk), Cpg, Chg, Ing, Adg, Tng, Tpyg and Ttpg; wherein: VaI is α-L/D-valine, lie is α-L/D-isoleucine, allo-lle is α-L/D-allo- isoleucine, Tie is α-L/D-ferf-leucine, 3-Peg is α-L/D-3-pentylglycine, Tpg is α-L/D-te/if-pentylglycine, Thr(O-alk) is any O-alkylated derivative of α-L/D-threonine, allo-Thr(O-alk) is any O-alkylated derivative of α-L/D-allo-threonine, Pen(S-alk) is any S-alkylated derivative of α-L/D-penicillamine, Cpg is α-L/D-cyclopentylglycine,

Chg is α-L/D-cyclohexylglycine, Ing is α-L/D-indanylglycine, Adg is α- L/D-adamantylglycine, Tng is α-L/D-tetrahydronaphthylglycine, Tpyg

is α-L/D-tetrahydropyranylglycine and Ttpg is α-L/D- tetrahydrothiopyranylglycine.

However, in all of those cases where the amyloid-binding peptide sequence possesses or comprises this second, but none of the other four alternative essential features described herein, no more than one, or preferably none of the amino acid residues in the amyloid-binding peptide sequence is any form of a phenylalanine residue. It has been found that such peptide sequences, which comprise two or more phenylalanine residues, are highly insoluble compared with related peptide sequences which comprise only one phenylalanine residue, and especially compared with related peptide sequences which comprise no phenylalanine residues. Moreover, several of those related peptide sequences comprising two or more phenylalanine residues were inherently toxic to cells in vitro, possibly due to oxidation of their phenylmethyl side chains. This dependent feature (i.e., that no more than one of the amino acid residues in the amyloid-binding peptide sequence is a phenylalanine residue) is preferred, but not essential in any cases where the amyloid-binding peptide sequence possesses or comprises any one or more of the other four alternative essential features described herein.

2.3(Hi). Third alternative essential feature of the invention.

Regarding the third alternative essential feature of the present invention (see iii above), at least one of the amino acid residues in the amyloid- binding peptide sequence has a hydrophobic side chain which comprises 2 or 3 non-hydrogen atoms that are attached directly to a β-carbon atom by single covalent bonds, and 5 or more carbon atoms in total. Thus, according to the definitions provided above, the side chain(s) of at least one amino acid residue in the amyloid-binding peptide sequence each comprise: a β-carbon atom; 2 or 3 carbon, nitrogen, oxygen, sulphur or other non-hydrogen atoms (excluding the α-carbon atom of each amino acid residue), which are attached directly to the β-carbon by single covalent bonds; and 5 or more carbon atoms in total. By way of example, suitable amino acid residues that fall into this category include, but are not limited to: 3-Peg, Tpg, Cpg, Chg, Ing, Adg, Tng, Tpyg and Ttpg; and potentially also Thr(O-alk), allo-Thr(O-alk) and Pen(S-alk) (provided that the O/S alkyl groups are large enough to qualify); wherein the definitions provided above (for examples given under point ii) are again applied here.

2.3(iv). Fourth alternative essential feature of the invention.

With respect to the fourth alternative essential feature of the present invention (point iv above), at least one amino acid residue in the amyloid- binding peptide sequence has a hydrophobic side chain comprising 3 non- hydrogen atoms that are attached directly to a β-carbon atom by single covalent bonds. This means that the side chain(s) of at least one amino acid residue in the amyloid-binding peptide sequence each comprise: a β-

carbon atom; plus any number of additional atoms, including 3 carbon, nitrogen, oxygen, sulphur or other non-hydrogen atoms (excluding any α- carbon atoms), which are attached directly to the β-carbon by single covalent bonds. By way of example, suitable amino acid residues that fall into this category include, but are not limited to:

Tie, Tpg, Pen(S-alk) and Adg; wherein the definitions provided above (for examples given under point ii) are again applied here.

2.3(v). Fifth alternative essential feature of the invention.

According to the fifth alternative essential feature of the present invention (point v above), at least one of the amino acid residues in the amyloid- binding peptide sequence has a hydrophobic side chain comprising a cyclic aliphatic ring, which is attached directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond. The term

"cyclic aliphatic ring" herein refers to any non-aromatic ring of atoms. A cyclic aliphatic ring may therefore include any non-aromatic ring which is either: monocyclic, bicyclic, tricyclic, or otherwise fused or connected directly to one or more aromatic or cyclic aliphatic rings; 3-membered, 4- membered, 5-membered, 6-membered, 7-membered or 8-membered; homocyclic or heterocyclic; symmetric or asymmetric; saturated or unsaturated; and optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents. Thus, according to this definition, at least 1 amino acid residue in the amyloid-binding peptide sequence comprises any non- aromatic ring which is attached directly to the peptide backbone of the amyloid-binding peptide sequence (more specifically to the α-carbon atom of the amino acid residue, which forms part of the peptide backbone) by a single covalent bond. By way of example, suitable amino acid residues that fall into this category include, but are not limited to: Cpg, Chg, Ing, Adg, Tng, Tpyg and Ttpg; wherein the definitions provided above (for examples given under point ii) are again applied here.

Although the amyloid-binding peptide sequence may comprise or possess any one, and only one of the five alternative essential features of the invention described above, the amyloid-binding peptide sequence preferably possesses or comprises any combination of 2, preferably 3, more preferably 4, or ideally all 5 of these features. Moreover, although all of these features are technically distinct from one another and may be considered separately, many examples of suitable amino acid residues comprise or possess 2, 3, 4, or potentially all of these features. For example:

Tpg and potentially also Pen(S-alk) possess alternative essential features ii, iii and iv;

Cpg, Chg, Ing, Tng, Tpyg and Ttpg possess alternative essential features ii, iii and v;

Adg possess alternative essential features ii, iii, iv and v; and

all of these amino acid residues may also contribute towards alternative essential feature i.

Consequently, amyloid-binding peptide sequences comprising these amino acid residues are highly preferred. However these specific examples are provided for guidance only. It will be appreciated that the general inventive concept lies in the provision of chemical compounds or compositions comprising amino acid residues, and combinations thereof, which possess at least one, and preferably more, of the alternative essential features, as described above. Additonal features described herein may be present in the chemical compounds or compositions of the present invention either independently or, where appropriate, in combination with any other feature.

2.4. Definition and length of amyloid-binding peptide sequence

The amyloid-binding peptide sequence is defined as any peptide sequence which, in the context of the chemical compound or composition as a whole, binds to, or otherwise associates with a target amyloid-forming protein or peptide. Where a high binding affinity for the target amyloid-forming protein or peptide is required, the amyloid-binding peptide sequence is preferably the four-residue amino acid sequence X2-X3-X4-X5, or more preferably the five-residue amino acid sequence X1-X2-X3-X4-X5. Where low molecular weight is required, the amyloid-binding peptide sequence is preferably the four-residue amino acid sequence X2-X3-X4-X5, or more preferably the 3- residue amino acid sequence X3-X4-X5. And where both high binding affinity and low molecular weight are required (for diagnostic or therapeutic use of the compounds in vivo, for example) the amyloid-binding peptide sequence is preferably the 4-residue amino acid sequence X2-X3-X4-X5.

Preferably, all the amino acid residues in the amyloid-binding peptide sequence play a significant role in the binding of the amyloid-binding peptide sequence to the target amyloid-forming protein or peptide or to a specific target amino acid sequence within the target amyloid-forming protein or peptide. For example, the side chain of each amino acid residue in the amyloid-binding peptide sequence is preferably selected to form a substantial hydrophobic interaction with one or more hydrophobic side chains of a target amino acid sequence. In this case, a "substantial hydrophobic interaction" means any intermolecular hydrophobic interaction that directly involves at least 2, preferably 3, more preferably 4, or ideally 5 or more CH, CH ₂ or CH ₃ groups within the side chain of an amino acid residue in the amyloid-binding peptide sequence.

Where amino acid residues in the amyloid-binding peptide sequence are modified, the number of modified residues is identified by either a percentage of the residues in the amyloid-binding peptide sequence or by a specific number of residues.

In cases where a percentage is used to identify the number of modified residues, and the percentage does not relate to a whole number of residues, the percentage is intended to cover the higher number of residues in the amyloid-binding peptide sequence. This is highlighted by use of the terms "at least", "or more" or "more than". For example, at least 60% of the residues in a 5-residue amino acid sequence would be 3 or more residues

and at least 60% of the residues in a 3-residue amino acid sequence would be 2 or 3 residues.

2.5. Form and stereochemistry of amino acid residues Each amino acid residue in the amyloid-binding peptide sequence may be any form of amino acid residue, provided that the amyloid-binding peptide sequence possesses all the essential features of the invention described herein. For example, the amyloid-binding peptide sequence may comprise 1 , 2, 3, 4, or potentially 5 β-amino acid residues (NH-CH ₂ -CH(R)-CO), wherein a β-NH group is connected to the α-carbonyl (CO) group by two carbon atoms, one of which is the α-carbon atom to which the side chain (R) is directly attached. In the most preferred embodiment of the present invention, however, at least 1 or 2, preferably 3 or 4, or ideally all of the amino acid residues in the amyloid-binding peptide sequence are α-amino acid residues (NH-CH(R)-CO), wherein an α-NH group is connected to the α-carbonyl (CO) group by a single carbon atom (the α-carbon atom), to which the side chain (R) is directly attached.

In one embodiment of the invention, at least 1 , 2, 3, 4 or all of the amino acid residues in the amyloid-binding peptide sequence are α-L-amino acid residues. Alternatively, the amyloid-binding peptide sequence may be a

'mixed' sequence of α-L- and α-D-amino acid residues, consisting of one or more α-L-amino acid residues and one or more α-D-amino acid residues linked together in any order. For example, the amyloid-binding peptide sequence may be a sequence of 2, 3 or 4 consecutive α-L-amino acid residues, with one α-D-amino acid residue attached to either end, or a sequence of 2, 3 or 4 consecutive α-D-amino acid residues with a single α- L-amino acid residue attached to either end.

Preferably, the amyloid-binding peptide sequence comprises at least one α- D-amino acid residue. For example, the amyloid-binding peptide sequence may comprise at least 2, preferably 3 or 4, or potentially 5 α-D-amino acid residues. In the most preferred embodiment of the invention, all of the amino acid residues in the amyloid-binding peptide sequence are α-D- amino acid residues, so that the amyloid-binding peptide sequence is a sequence of 3, 4 or 5 consecutive α-D-amino acid residues, depending on the chosen length of the amyloid-binding peptide sequence.

In another embodiment of the present invention, the amyloid-binding peptide sequence comprises at least 1 , 2, 3, 4, or potentially 5 α,α- disubstituted α-amino acid residues, in which an additional hydrophobic side chain comprising 1 , 2, 3 or more carbon atoms is attached directly to the peptide backbone of the amyloid-binding peptide sequence (or more specifically, to the α-carbon atom of each amino acid residue, which forms part of the peptide backbone) by a single covalent bond.

Where chemical compounds or compositions are referred to herein, without specific reference to their stereochemistry, it is intended that the chemical compounds or compositions include each of any possible individual stereoisomer and/or racemic mixtures.

2.6. Non-natural peptide sequences and amino acids

The amyloid-binding peptide sequence of the chemical compounds or compositions of the present invention is not essentially derived from or based on any section of the target amyloid-forming protein or peptide to which the amyloid-binding peptide sequence binds.

The amyloid-binding peptide sequence may differ from every section of the target amyloid-forming protein or peptide, and every reversed, inversed, retro-inversed or scrambled sequence thereof, by at least 1 , 2, 3, 4 or 5 amino acid side chains. Furthermore, the amyloid-binding peptide sequence need not be essentially derived from or based on any naturally occurring amyloid-forming protein or peptide sequence, or any section thereof. It may differ from every naturally occurring amyloid-forming protein and peptide sequence, and every section and reversed, inversed, retro-inversed or scrambled sequence thereof, by at least 1 , 2, 3, 4 or 5 amino acid side chains.

The amyloid-binding peptide sequence may comprise at least 1 , 2, 3, 4 or 5 amino acid residues with non-natural amino acid side chains. Alternatively, the amyloid-binding peptide sequence comprises no more than 4, 3, 2 or 1 amino acid residues which have natural amino acid side chains. In another aspect, the amyloid-binding peptide sequence comprises no amino acid residues that have natural amino acid side chains.

2.7. Side chain and amino acid composition

In another aspect, the present invention provides a chemical compound or composition comprising an amyloid-binding peptide sequence wherein at least 1 , 2, 3, 4 or all of the amino acid residues in the amyloid-binding peptide sequence each have a hydrophobic side chain comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 or more carbon atoms in total. Therefore, at least 1 , 2, 3, 4 or all of the amino acid residues in the amyloid-binding peptide sequence may each have a hydrophobic side chain comprising 3 or more carbon atoms in total, 4 or more carbon atoms in total, 5 or more carbon atoms in total, 6 or more carbon atoms in total or 7, 8, 9, 10, 11 , 12 or more carbon atoms in total

At least 1 , 2, 3, 4 or all of the amino acid residues in the amyloid-binding peptide sequence may each have a hydrophobic side chain comprising no hydrogen bond donors. Furthermore, at least 1 , 2, 3, 4 or all of the amino acid residues in the amyloid-binding peptide sequence may each have a hydrophobic side chain comprising no more than one hydrogen bond acceptor. In another aspect, at least 1 , 2, 3, 4 or all of the amino acid residues in the amyloid-binding peptide sequence each have a hydrophobic side chain comprising no hydrogen bond acceptors.

Chemical compounds or compositions of the present invention may further comprise an amyloid-binding peptide sequence wherein, at least 1 , 2, 3, 4 or all of the amino acid residues in the amyloid-binding peptide sequence each have a hydrophobic side chain comprising no rotatable bonds, excluding a single covalent bond which links a β-carbon atom in the amino acid side chain to an α-carbon atom in the peptide backbone. Furthermore,

at least 1 , 2, 3, 4 or all of the amino acid residues in the amyloid-binding peptide sequence may each have a hydrophobic side chain comprising 2 or 3 non-hydrogen atoms that are attached directly to a β-carbon atom by single covalent bonds. As used herein, the term "rotatable bond" is intended to adopt its conventional meaning.

Possible hydrophobic side chains on at least 1 , 2, 3, 4 or all of the amino acid residues in the amyloid-binding peptide sequence can be selected from, but are not limited to, the group consisting of: (a) CH(R ^αi )(R ^α2 ), C(R ^α3 )(R°- ⁴ )(R ^α5 ), CH(R ^α6 )O(R ^α7 ), C(R ^α8 )(R ^α9 )O(R ^α10 ),

CH(R ^αi1 )S(R ⁰ - ¹² ) or C(R ^α13 )(R°- ¹⁴ )S(R ^α15 ), wherein R ^α \ R ⁰² , R ⁰³ , R ⁰⁴ , R ⁰⁵ , R ⁰⁶ , R ⁰⁷ , R ⁰⁸ , R ⁰⁹ , R ^{0 10} , R ^{0 11} , R ^α12 , R ^{0 13} , R ^{0 14} and R ^{0 15} are each independently selected from the group consisting of: i. any hydrophobic group comprising 1 , 2, 3, 4, 5, 6, 7, 8 or more carbon atoms in total; ii. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 3-pentyl, neopentyl, isopentyl, fert-pentyl, hexyl, or any other branched or straight-chain alkyl group; and iii. any hydrophobic group comprising an aromatic ring or cyclic aliphatic ring, which is optionally substituted with 1 , 2, 3, 4 or more substituents;

(b) any hydrophobic group comprising a cyclic aliphatic ring which is connected directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond. Further hydrophobic side chains can be independently selected from the group consisting of:

(a) isopropyl, sec-butyl, tert-butyl, 1-alkyloxyethyl, 2-aikyloxy-2-propyl, 1- alkylthioethyl or 2-alkylthio-2-propyl; and

(b) any group comprising a cyclic aliphatic ring which is independently selected from the group consisting of: cycloalkyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thioxetanyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, cyclohexyl, cycloheptyl, cyclooctyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, oxathianyl, morpholinyl, thiomorpholinyl, indanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, tetrahydronaphthyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzomorpholinyl, benzothiomorpholinyl, benzodioxanyl, benzodithianyl, benzoxathianyl, norbomyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl, bisnoradamantyl, twistanyl and twistbrendanyl; wherein the selected aliphatic ring is attached directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond, and is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents.

At least 1 , 2, 3, 4 or all of the amino acid residues in the amyloid-binding peptide sequence may each have a hydrophobic side chain comprising a

cyclic aliphatic ring that is attached directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond.

Furthermore, at least 1 , 2, 3, 4 or all of the amino acid residues in the amyloid-binding peptide sequence may be α-D-amino acid residues which are independently selected from the group consisting of:

D-VaI, D-IIe, D-allo-lle, D-TIe, D-3-Peg, D-Tpg, D-Thr(O-alk), D-allo- Thr(O-alk), D-Pen (S-alk), D-Cpg, D-Chg, D-lng, D-Adg, D-Tng, D- Tpyg, D-Ttpg and D-Phg; wherein: D-VaI is α-D-valine, D-IIe is α-D-isoleucine, D-allo-lle is α-D-allo- isoleucine, D-TIe is α-D-ferf-leucine, D-3-Peg is α-D-3-pentylglycine, D-Tpg is α-D-fert~pentylglycine, D-Thr(O-alk) is any O-alkylated derivative of α-D-threonine, D-allo-Thr(O-alk) is any O-alkylated derivative of α-D-allo-threonine, D-Pen(S-alk) is any S-alkylated derivative of α-D-penicillamine, D-Cpg is α-D-cyclopentylglycine, D-

Chg is α-D-cyclohexylglycine, D-lng is α-D-indanylglycine, D-Adg is α-D-adamantylglycine, D-Tng is α-D-tetrahydronaphthylglycine, D- Tpyg is α-D-tetrahydropyranylglycine, D-Ttpg is α-D- tetrahydrothiopyranylglycine and D-Phg is α-D-phenylglycine. Preferably, the amyloid-binding peptide sequence comprises: at least 1 , 2,

3, 4 or 5 α-D-isoleucine residues; at least 1, 2, 3, 4 or 5 α-D-allo-isoleucine residues; at least 1 , 2, 3, 4 or 5 α-D-te/f-leucine residues; at least 1, 2, 3, 4 or 5 α-D-cyclopentylglycine residues; at least 1 , 2, 3, 4 or 5 α-D- cyclohexylglycine residues; or at least 1, 2, 3, 4 or 5 α-D-indanylglycine residues, or any combination thereof.

The amyloid-binding peptide sequence may comprise no more than one α- L- or α-D-phenylalanine residue. Alternatively, the amyloid-binding peptide sequence comprises no α-L- or α-D-phenylalanine residues.

Furthermore, the amyloid-binding peptide sequences may comprise at least 1 , 2, 3, 4 or 5 amino acid residues that have non-aromatic amino acid side chains. Alternatively, the amyloid-binding peptide sequence comprises no more than 4, 3, 2 or 1 amino acid residues that have aromatic amino acid side chains. In anoter aspect, the amyloid-binding peptide sequence may comprise no amino acid residues that have aromatic amino acid side chains.

2.8. Selection of X1 side chain and amino acid residue

The amino acid residue X1 may have a number of suitable side chains. Where appropriate, the side chains may comprise one or more of the following features.

In one aspect of the invention, the side chain of X1 may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more carbon atoms in total.

In another aspect, the side chain of X1 may comprise no hydrogen bond donors. Furthermore, the side chain of X1 may comprise no more than one hydrogen bond acceptor, or no hydrogen bond acceptors.

It is also possible for the side chain of X1 to comprise no rotatable bonds, excluding a single covalent bond which links a β-carbon atom in the amino acid side chain to an α-carbon atom in the peptide backbone.

The side chain of X1 may, further, comprise 2 or 3 non-hydrogen atoms which are attached directly to a β-carbon atom by single covalent bonds.

Side chains of X1 can be selected from, but are not limited to, the group consisting of:

(a) CH(R ^{1 1} )(R ¹ - ² ), C(R ¹³ )(R ^{1 4} )(R ¹ - ⁵ ), CH(R ^{1 f3} )O(R ¹ - ⁷ ), C(R ^{1 8} )(R ¹ - ⁹ )O(R ¹ - ¹⁰ ), CH(R ^{1 11} )S(R ¹¹² ) or C(R ¹¹³ )(R ¹ - ¹⁴ )S(R ¹ - ¹⁵ ), wherein R ^{1 1} , R ¹ - ² , R ¹³ , R ^{1 4} , R ¹ - ⁵ , R ¹ - ⁶ , R ¹⁷ , R ¹ - ⁸ , R ¹ - ⁹ , R ¹ - ¹⁰ , R ¹¹¹ , R ^{1 12} , R ^{1 13} , R ¹¹⁴ and R ^{1 15} are each independently selected from the group consisting of: i. any hydrophobic group comprising 1, 2, 3, 4, 5, 6, 7, 8 or more carbon atoms in total; ii. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terf-butyl, pentyl, 3-pentyl, neopentyl, isopentyl, fe/f-pentyl, hexyl, or any other branched or straight-chain alkyl group; and iii. any hydrophobic group comprising an aromatic ring or cyclic aliphatic ring, which is optionally substituted with 1, 2, 3, 4 or more substituents; and (b) any hydrophobic group comprising a cyclic aliphatic ring which is connected directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond.

Further side chains of X1 can be selected from the group consisting of:

(a) isopropyl, sec-butyl, ferf-butyl, 1-alkyloxyethyl, 2-alkyloxy-2-propyl, 1- alkylthioethyl or 2-alkylthio-2-propyl; and

(b) any group comprising a cyclic aliphatic ring which is independently selected from the group consisting of: cycloalkyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thioxetanyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, cyclohexyl, cycloheptyl, cyclooctyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, oxathianyl, morpholinyl, thiomorpholinyl, indanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, tetrahydronaphthyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzomorpholinyl, benzothiomorpholinyl, benzodioxanyl, benzodithianyl, benzoxathianyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl, bisnoradamantyl, twistanyl and twistbrendanyl; wherein the selected aliphatic ring is attached directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond, and is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents.

When the side chain of X1 comprises a cyclic aliphatic ring, the cyclic aliphatic ring may be attached directly to the α-carbon atom of X1 by a single covalent bond.

X1 may also be an α-D-amino acid residue. When X1 is an α-D-amino acid residue, it may be selected from the group consisting of, but not limited to:

D-VaI, D-IIe, D-allo-lle, D-TIe, D-3-Peg, D-Tpg, D-Thr(O-alk), D-allo- Thr(O-alk), D-Pen (S-alk), D-Cpg, D-Chg, D-lng, D-Adg, D-Tng, D- Tpyg, D-Ttpg and D-Phg; wherein:

D-VaI is α-D-valine, D-IIe is α-D-isoleucine, D-allo-lle is α-D-allo- isoleucine, D-TIe is α-D-ferf-leucine, D-3-Peg is α-D-3-pentylglycine, D-Tpg is α-D-fe/if-pentylglycine, D-Thr(O-alk) is any O-alkylated derivative of α-D-threonine, D-allo-Thr(O-alk) is any O-alkylated derivative of α-D-allo-threonine, D-Pen(S-alk) is any S-alkylated derivative of α-D-penicill-amine, D-Cpg is α-D-cyclopentylglycine, D- Chg is α-D-cyclohexylglycine, D-lng is α-D-indanylglycine, D-Adg is α-D-adamantylglycine, D-Tng is α-D-tetrahydronaphthylglycine, D- Tpyg is α-D-tetrahydropyranylglycine, D-Ttpg is α-D- tetrahydrothiopyranylglycine and D-Phg is α-D-phenylglycine.

In compounds or compositions of the present invention, X1 is preferably: α- D-isoleucine, α-D-allo-isoleucine, α-D-te/f-leucine, α-D-cyclopentylglycine, α-D-cyclohexylglycine or α-D-indanylglycine. The present invention may also relate to compounds or compositions, wherein X1 is not a phenylalanine residue or wherein X1 has a non- aromatic side chain, as well as relating to compounds or compositions, wherein X1 has a non-natural side chain.

2.9. Selection of X2 side chain and amino acid residue

The amino acid residue X2 may have a number of suitable side chains. Where appropriate, the side chains may comprise one or more of the following features.

In one aspect of the present invention the side chain of X2 may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more carbon atoms in total.

In anither aspect of the inventoin, the side chain of X2 may comprise no hydrogen bond donors. Furthermore, the side chain of X2 comprises no more than one hydrogen bond acceptor, or no hydrogen bond acceptors.

It is also possible for the side chain of X2 to comprise no rotatable bonds, excluding a single covalent bond which links a β-carbon atom in the amino acid side chain to an α-carbon atom in the peptide backbone.

The side chain of X2 may, further, comprise 2 or 3 non-hydrogen atoms which are attached directly to a β-carbon atom by single covalent bonds.

Side chains of X2 may be selected from, but are not limited to, the group consisting of:

(a) CH(R ² - ¹ )(R ²² ), C(R ²³ )(R ^Z4 )(R ² - ⁵ ), CH(R ^{2 f3} )O(R ^2J ), C(R ^{2 fJ} )(R ^Z9 )O(R ² - ¹⁰ ), CH(R ^{2 11} )S(R ² - ¹² ) or C(R ^{2 13} )(R ^Z14 )S(R ² - ¹⁵ ), wherein R ²¹ , R ²² , R ²³ , R ²⁴ , R ² - ⁵ , R ² - ⁶ , R ² - ⁷ , R ² - ⁸ , R ² - ⁹ , R ² - ¹⁰ , R ² - ¹¹ , R ^{2 12} , R ^{2 13} , R ²¹⁴ and R ^{2 15} are each independently selected from the group consisting of:

,

i. any hydrophobic group comprising 1 , 2, 3, 4, 5, 6, 7, 8 or more carbon atoms in total; ii. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fe/t-butyl, pentyl,

3-pentyl, neopentyl, isopentyl, te/t-pentyl, hexyl, or any other branched or straight-chain alkyl group; and iii. any hydrophobic group comprising an aromatic ring or cyclic aliphatic ring, which is optionally substituted with 1 , 2, 3, 4 or more substituents; and

(b) any hydrophobic group comprising a cyclic aliphatic ring which is connected directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond.

Further side chains of X2 can be selected from the group consisting of:

(a) isopropyl, sec-butyl, terf-butyl, 1-alkyloxyethyl, 2-alkyloxy-2-propyl, 1- alkylthioethyl or 2-alkylthio-2-propyl; and (b) any group comprising a cyclic aliphatic ring which is independently selected from the group consisting of: cycloalkyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thioxetanyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, cyclohexyl, cycloheptyl, cyclooctyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, oxathianyl, morpholinyl, thiomorpholinyl, indanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, tetrahydronaphthyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, tetrahydroquinolinyi, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzomorpholinyl, benzothiomorpholinyl, benzodioxanyl, benzodithianyl, benzoxathianyl, norbomyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl, bisnoradamantyl, twistanyl and twistbrendanyl; wherein the selected aliphatic ring is attached directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond, and is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents.

When, the side chain of X2 comprises a cyclic aliphatic ring, the cyclic aliphatic ring may be attached directly to the α-carbon atom of X2 by a single covalent bond. X2 may also be an α-D-amino acid residue. When X2 is an α-D-amino acid residue it can be selected from the group consisting of, but not limited to:

D-VaI, D-IIe, D-allo-lle, D-TIe, D-3-Peg, D-Tpg, D-Thr(O-alk), D-allo- Thr(O-alk), D-Pen (S-alk), D-Cpg, D-Chg, D-lng, D-Adg, D-Tng, D- Tpyg, D-Ttpg and D-Phg; wherein:

D-VaI is α-D-valine, D-IIe is α-D-isoleucine, D-allo-lle is α-D-allo- isoleucine, D-TIe is α-D-fert-leucine, D-3-Peg is α-D-3-pentylglycine, D-Tpg is α-D-terf-pentylglycine, D-Thr(O-alk) is any O-alkylated derivative of α-D-threonine, D-allo-Thr(O-alk) is any O-alkylated derivative of α-D-allo-threonine, D-Pen(S-alk) is any S-alkylated derivative of α-D-penicill-amine, D-Cpg is α-D-cyclopentylglycine, D-

Chg is α-D-cyclohexylglycine, D-lng is α-D-indanylglycine, D-Adg is α-D-adamantylglycine, D-Tng is α-D-tetrahydronaphthylglycine, D- Tpyg is α-D-tetrahydropyranylglycine, D-Ttpg is α-D- tetrahydrothiopyranylglycine and D-Phg is α-D-phenylglycine. In compounds or compositions of the present invention X2 is preferably α-

D-isoleucine, α-D-allo-isoleucine, α-D-ferf-leucine, α-D-cyclopentylglycine, α-D-cyclohexylglycine or α-D-indanylglycine.

The present invention may also relate to compounds or compositions, wherein X2 is not a phenylalanine residue or wherein X2 has a non- aromatic side chain, as well as relating to compounds or compositions wherein X2 has a non-natural side chain.

2.10. Selection of X3 side chain and amino acid residue

The amino acid residue X3 may have a number of suitable side chains. Where appropriate, the side chains may comprise one or more of the following features.

In one aspect of the invention, the side chain of X3 may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 or more carbon atoms in total.

In another aspect of the invention, the side chain of X3 may comprise no hydrogen bond donors. Furthermore, the side chain of X3 may comprise no more than one hydrogen bond acceptor or no hydrogen bond acceptors.

It is also possible for the side chain of X3 to comprise no rotatable bonds, excluding a single covalent bond which links a β-carbon atom in the amino acid side chain to an α-carbon atom in the peptide backbone. The side chain of X3 may, further, comprise 2 or 3 non-hydrogen atoms which are attached directly to a β-carbon atom by single covalent bonds.

Side chains of X3 may be selected from, but are not limited to, the group consisting of:

(a) CH(R ^{3 1} XR ³² ), C(R ³ - ³ )(R ³ - ⁴ )(R ³ - ⁵ ), CH(R ^a6 )O(R ³ - ⁷ ), C(R ³ - ⁸ )(R ³⁹ )O(R ³ - ¹⁰ ), CH(R ^{3 11} )S(R ³ - ¹² ) or C(R ³ - ¹³ )(R ^{3 14} )S(R ³ - ¹⁵ ), wherein R ^{3 1} , R ³² , R ³³ , R ³⁴ ,

R ³ - ⁵ , R ³ - ⁶ , R ³⁷ , R ³ - ⁸ , R ³ - ⁹ , R ³ - ¹⁰ , R ³ - ¹¹ , R ^{3 12} , R ^{3 13} , R ^{3 14} and R ^{3 15} are each independently selected from the group consisting of: i. any hydrophobic group comprising 1 , 2, 3, 4, 5, 6, 7, 8 or more carbon atoms in total; ii. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terf-butyl, pentyl,

3-pentyl, neopentyl, isopentyl, fe/f-pentyl, hexyl, or any other branched or straight-chain alkyl group; and iii. any hydrophobic group comprising an aromatic ring or cyclic aliphatic ring, which is optionally substituted with 1 , 2, 3, 4 or more substituents; and

(b) any hydrophobic group comprising a cyclic aliphatic ring which is connected directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond.

Further side chains of X3 can be selected from the group consisting of:

(a) isopropyl, sec-butyl, tert-butyl, 1-alkyloxyethyl, 2-alkyloxy-2-propyl, 1- alkylthioethyl or 2-alky!thio-2-propyl; and

(b) any group comprising a cyclic aliphatic ring which is independently selected from the group consisting of: cycloalkyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thioxetanyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, cyclohexyl, cycloheptyl, cyclooctyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, oxathianyl, morpholinyl, thiomorpholinyl, indanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, tetrahydronaphthyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzomorpholinyl, beήzothiomorpholinyl, benzodioxanyl, benzodithianyl, benzoxathianyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl, bisnoradamantyl, twistanyl and twistbrendanyl; wherein the selected aliphatic ring is attached directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond, and is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents. When, the side chain of X3 comprises a cyclic aliphatic ring, the cyclic aliphatic ring may be attached directly to the α-carbon atom of X3 by a single covalent bond.

X3 may also be an α-D-amino acid residue. When X3 is an α-D-amino acid residue, it can be selected from the group consisting of, but not limited to: D-VaI ₁ D-IIe, D-allo-lle, D-TIe, D-3-Peg, D-Tpg, D-Thr(O-alk), D-allo-

Thr(O-alk), D-Pen (S-alk), D-Cpg, D-Chg, D-lng, D-Adg, D-Tng, D- Tpyg, D-Ttpg and D-Phg; wherein:

D-VaI is α-D-valine, D-IIe is α-D-isoleucine, D-allo-lle is α-D-allo- isoleucine, D-TIe is α-D-ferf-leucine, D-3-Peg is α-D-3-pentylglycine,

D-Tpg is α-D-te/f-pentylglycine, D-Thr(O-alk) is any O-alkylated derivative of α-D-threonine, D-allo-Thr(O-alk) is any O-alkylated derivative of α-D-allo-threonine, D-Pen(S-alk) is any S-alkylated derivative of α-D-penicill-amine, D-Cpg is α-D-cyclopentylglycine, D- Chg is α-D-cyclohexylglycine, D-lng is α-D-indanylglycine, D-Adg is α-D-adamantylglycine, D-Tng is α-D-tetrahydronaphthylglycine, D- Tpyg is α-D-tetrahydropyranylglycine, D-Ttpg is α-D- tetrahydrothiopyranylglycine and D-Phg is α-D-phenylglycine.

In compounds or compositions of the present invention, X3 is preferably α- D-isoleucine, α-D-allo-isoleucine, α-D-te/f-leucine, α-D-cyclopentylglycine, α-D-cyclohexylglycine or α-D-indanylglycine.

The present invention may also relate to compounds or compositions, wherein X3 is not a phenylalanine residue or wherein X3 has a non- aromatic side chain, as well as relating to compounds or compositions, wherein X3 has a non-natural side chain.

2.11. Selection of X4 side chain and amino acid residue

The amino acid residue X4 may have a number of suitable side chains. Where appropriate, the side chains may comprise one or more of the following features. In one aspect of the invention the side chain of X4 may comprise 3, 4, 5, 6,

7, 8, 9, 10, 11 , 12 or more carbon atoms in total.

In another aspect of the invention, the side chain of X4 may comprise no hydrogen bond donors. Furthermore, the side chain of X4 comprises no more than one hydrogen bond acceptor or no hydrogen bond acceptors. It is also possible for the side chain of X4 to comprise no rotatable bonds, excluding a single covalent bond which links a β-carbon atom in the amino acid side chain to an α-carbon atom in the peptide backbone.

The side chain of X4 may, further, comprise 2 or 3 non-hydrogen atoms which are attached directly to a β-carbon atom by single covalent bonds. Side chains of X4 may be selected from, but are not limited to, the group consisting of:

(a) CH(R ^{4 1} )(R ⁴ - ² ), C(R ⁴³ )(R ⁴ - ⁴ )(R ⁴ - ⁵ ), CH(R ⁴⁶ )O(R ⁴ - ⁷ ), C(R ⁴ - ⁸ )(R ⁴⁹ )O(R ⁴ - ¹⁰ ), CH(R ^{4 11} )S(R ⁴ - ¹² ) or C(R ⁴ - ¹³ )(R ⁴¹⁴ )S(R ⁴ - ¹⁵ ), wherein R ^{4 1} , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴ - ⁵ , R ⁴ - ⁶ , R ⁴ - ⁷ , R ⁴ - ⁸ , R ⁴ - ⁹ , R ⁴ - ¹⁰ , R ⁴ - ¹¹ , R ^{4 12} , R ^{4 13} , R ^{4 14} and R ^{4 15} are each independently selected from the group consisting of: i. any hydrophobic group comprising 1 , 2, 3, 4, 5, 6, 7, 8 or more carbon atoms in total; ii. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ferf-butyl, pentyl,

3-pentyl, neopentyl, isopentyl, terf-pentyl, hexyl, or any other branched or straight-chain alkyl group; and iii. any hydrophobic group comprising an aromatic ring or cyclic aliphatic ring, which is optionally substituted with 1 , 2, 3, 4 or more substituents; and

(b) any hydrophobic group comprising a cyclic aliphatic ring which is connected directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond.

Further side chains of X4 can be selected from the group consisting of:

(a) isopropyl, sec-butyl, tert-butyl, 1-alkyloxyethyl, 2-alkyloxy-2-propyl, 1- alkylthioethyl or 2-alkylthio-2-propyl; and (b) any group comprising a cyclic aliphatic ring which is independently selected from the group consisting of: cycloalkyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thioxetanyl, cyclopentyl, pyrrolidinyi, tetrahydrofuranyl, tetrahydrothienyl, cyclohexyl, cycloheptyl, cyclooctyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, oxathianyl, morpholinyl, thiomorpholinyl, indanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, tetrahydronaphthyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzomorpholinyl,

benzothiomorpholinyl, benzodioxanyl, benzodithianyl, benzoxathianyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl, bisnoradamantyl, twistanyl and twistbrendanyl; wherein the selected aliphatic ring is attached directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond, and is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents.

When, the side chain of X4 comprises a cyclic aliphatic ring, the cyclic aliphatic ring may be attached directly to the α-carbon atom of X4 by a single covalent bond. X4 may also be an α-D-amino acid residue. When X4 is an α-D-amino acid residue, it can be selected from the group consisting of, but not limited to:

D-VaI, D-IIe, D-allo-lle, D-TIe, D-3-Peg, D-Tpg, D-Thr(O-alk), D-allo- Thr(O-alk), D-Pen (S-alk), D-Cpg, D-Chg, D-lng, D-Adg, D-Tng, D- Tpyg, D-Ttpg and D-Phg; wherein:

D-VaI is α-D-valine, D-IIe is α-D-isoleucine, D-allo-lle is α-D-allo- isoleucine, D-TIe is α-D-fe/f-leucine, D-3-Peg is α-D-3-pentylglycine, D-Tpg is α-D-fe/f-pentylglycine, D-Thr(O-alk) is any O-alkylated derivative of α-D-threonine, D-allo-Thr(O-alk) is any O-alkylated derivative of α-D-allo-threonine, D-Pen(S-alk) is any S-alkylated derivative of α-D-penicill-amine, D-Cpg is α-D-cyclopentylglycine, D- Chg is α-D-cyclohexylglycine, D-lng is α-D-indanylglycine, D-Adg is α-D-adamantylglycine, D-Tng is α-D-tetrahydronaphthylglycine, D- Tpyg is α-D-tetrahydropyranylglycine, D-Ttpg is α-D- tetrahydrothiopyranylglycine and D-Phg is α-D-phenylglycine.

In compounds or compositions of the present invention X4 is preferably α- D-isoleucine, α-D-allo-isoleucine, α-D-te/f-leucine, α-D-cyclopentylglycine, α-D-cyclohexylglycine or α-D-indanylglycine.

The present invention may also relate to compounds or compositions, wherein X4 is not a phenylalanine residue or wherein X4 has a non- aromatic side chain, as well as relating to compounds or compositions, wherein X4 has a non-natural side chain.

2.12. Selection of X5 side chain and amino acid residue The amino acid residue X5 may have a number of suitable side chains.

Where appropriate, the side chains may comprise one or more of the following features.

In one aspect of the invention the side chain of X5 may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more carbon atoms in total. In another aspect of the invention, the side chain of X5 may comprise no hydrogen bond donors. Furthermore, the side chain of X5 comprises no more than one hydrogen bond acceptor or no hydrogen bond acceptors.

It is also possible for the side chain of X5 to comprise no rotatable bonds, excluding a single covalent bond which links a β-carbon atom in the amino acid side chain to an α-carbon atom in the peptide backbone.

The side chain of X5 may, further, comprise 2 or 3 non-hydrogen atoms which are attached directly to a β-carbon atom by single covalent bonds.

Side chains of X5 may be selected from, but are not limited to, the group consisting of: (a) CH(R ⁵¹ )(R ⁵ - ² ), C(R ⁵³ )(R ⁵ - ⁴ )(R ⁵ - ⁵ ), CH(R ⁵⁶ )O(R ⁵ - ⁷ ), C(R ⁵ - ⁸ )(R ^5'9 )O(R ⁵ - ¹⁰ ),

CH(R ^{5 11} )S(R ⁵ - ¹² ) or C(R ^{5 13} )(R ⁵ - ¹⁴ )S(R ⁵ - ¹⁵ ), wherein R ^{5 1} , R ⁵² , R ⁵³ , R ⁵ ^ ₁ R ⁵ - ⁵ , R ⁵ - ⁶ , R ⁵ - ⁷ , R ⁵ - ⁸ , R ⁵ - ⁹ , R ⁵ - ¹⁰ , R ⁵ - ¹¹ , R ^{5 12} , R ⁵¹³ , R ^{5 14} and R ^{5 15} are independently selected from the group consisting of: i. any hydrophobic group comprising 1 , 2, 3, 4, 5, 6, 7, 8 or more carbon atoms in total; ii. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fe/f-butyl, pentyl, 3-pentyl, neopentyl, isopentyl, tert-pentyl, hexyl, or any other branched or straight-chain alkyl group; and iii. any hydrophobic group comprising an aromatic ring or cyclic aliphatic ring, which is optionally substituted with 1 , 2, 3, 4 or more substituents; and

(b) any hydrophobic group comprising a cyclic aliphatic ring which is connected directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond. Further side chains of X5 can be selected from the group consisting of:

(a) isopropyl, sec-butyl, tert-butyl, 1-alkyloxyethyl, 2-alkyloxy-2-propyl, 1- alkylthioethyl or 2-alkylthio-2-propyl; and

(b) any group comprising a cyclic aliphatic ring which is independently selected from the group consisting of: cycloalkyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thioxetanyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, cyclohexyl, cycloheptyl, cyclooctyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, oxathianyl, morpholinyl, thiomorpholinyl, indanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, tetrahydronaphthyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzomorpholinyl, benzothiomorpholinyl, benzodioxanyl, benzodithianyl, benzoxathianyl, norbomyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl, bisnoradamantyl, twistanyl and twistbrendanyl; wherein the selected aliphatic ring is attached directly to the peptide backbone of the amyloid-binding peptide sequence by a single covalent bond, and is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents. When, the side chain of X5 comprises a cyclic aliphatic ring, the cyclic aliphatic ring may be attached directly to the α-carbon atom of X5 by a single covalent bond.

X5 may also be an α-D-amino acid residue. When X5 is an α-D-amino acid residue, it can be selected from the group consisting of, but not limited to:

D-VaI ₁ D-IIe, D-allo-lle, D-TIe, D-3-Peg, D-Tpg, D-Thr(O-alk), D-allo- Thr(O-alk), D-Pen (S-alk), D-Cpg, D-Chg, D-lng, D-Adg, D-Tng, D- Tpyg, D-Ttpg and D-Phg; wherein: D-VaI is α-D-valine, D-IIe is α-D-isoleucine, D-allo-lle is α-D-allo- isoleucine, D-TIe is α-D-terf-leucine, D-3-Peg is α-D-3-pentyiglycine, D-Tpg is α-D-terf-pentylglycine, D-Thr(O-alk) is any O-alkylated derivative of α-D-threonine, D-allo-Thr(O-alk) is any O-alkylated derivative of α-D-allo-threonine, D-Pen(S-alk) is any S-alkylated derivative of α-D-penicill-amine, D-Cpg is α-D-cyclopentylglycine, D-

Chg is α-D-cyclohexylglycine, D-lng is α-D-indanylglycine, D-Adg is α-D-adamantylglycine, D-Tng is α-D-tetrahydronaphthylglycine, D- Tpyg is α-D-tetrahydropyranylglycine, D-Ttpg is α-D- tetrahydrothiopyranylglycine and D-Phg is α-D-phenylglycine. In compounds or compositions of the present invention, X5 is preferably α-

D-isoleucine, α-D-allo-isoleucine, α-D-ferf-leucine, α-D-cyclopentylglycine, α-D-cyclohexylglycine or α-D-indanylglycine.

The present invention may also relate to compounds or compositions, wherein X5 is not a phenylalanine residue or wherein X5 has a non- aromatic side chain, as well as relating to compounds or compositions, wherein X5 has a non-natural side chain.

2.13. Alternative side chains and amino acid residues

In a further aspect, the present invention provides chemical compounds or compositions wherein any 1 , 2 or more remaining, unspecified side chains of amino acid residues in the amyloid-binding peptide sequence are each independently selected from the group consisting of, but not limited to:

(a) ethyl, propyl, butyl, isobutyl, pentyl, neopentyl, isopentyl, hexyl, or any other branched or straight-chain alkyl group comprising 2, 3, 4, 5, 6, 7, 8 or more carbon atoms in total;

(b) methoxyethyl, ethoxyethyl, or any other alkyloxyalkyl or aryloxyalkyl group;

(c) ethylthiomethyl, methylthioethyl, or any other alkylthioalkyl or arylthioalkyl group; (d) phenylmethyl, phenylethyl, 4-hydroxyphenylmethyl, 4- alkoxyphenylmethyl, indolylmethyl, 1-naphthylmethyl, 2- naphthylmethyl, or any other arylmethyl, arylethyl or arylaikyl group, optionally substituted with 1 , 2, 3, 4 or more substituents;

(e) cyclopentylmethyl, cyclohexylmethyl, or any other (cycloalkyl)methyl, (cycloalkyl)ethyl or (cycloalkyl)alkyl group, optionally substituted with

1 , 2, 3, 4 or more substituents; and

(f) CH ₂ (R ^{0 16} ), CH ₂ O(R ^{0 17} ), CH ₂ S(R ^0'18 ), CH ₂ CH ₂ (R ^{0 19} ), CH ₂ CH ₂ O(R ⁰²⁰ ), CH ₂ CH ₂ S(R ⁰²¹ ), wherein R ⁰¹⁶ , R ^0'17 , R ^{0 18} , R ⁰¹⁹ , R ⁰²⁰ and R ⁰²¹ are each independently selected from the group consisting of:

i. any hydrophobic group comprising 1 , 2, 3, 4, 5, 6, 7, 8 or more carbon atoms in total; ii. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fe/τf-butyl, pentyl,

3-pentyl, neopentyl, isopentyl, fert-pentyl, hexyl, or any other branched or straight-chain alkyl group; and iii. any hydrophobic group comprising an aromatic ring or cyclic aliphatic ring, which is optionally substituted with 1 , 2, 3, 4 or more substituents.

1 , 2 or more of any remaining, unspecified amino acid residues in the amyloid-binding peptide sequence may be α-D-amino acid residues having non-natural amino acid side chains.

Furthermore, 1 , 2 or more of any remaining, unspecified amino acid residues in the amyloid-binding peptide sequence may be each independently selected from the group consisting of, but not limited to: D-Cpa, D-Cha, D-Phe(x), D-Hphe, D-Tyr(O-alk), D-Htyr(O-alk), D-2-

PaI, D-3-Pal, D-4-Pal, D-Bip, D-Bpa, D-Dht, D-Tha, D-Bta, D-1-Nal, D-2-Nal and D-2-Qal; wherein:

D-Cpa is α-D-β-(cyclopentyl)alanine, D-Cha is α-D-β- (cyclohexyl)alanine, D-Phe(x) is any mono-, di-, tri- or polysubstituted derivative of α-D-phenylalanine, D-Hphe is α-D-homophenylalanine, D-Tyr(O-alk) is any O-alkylated derivative of α-D-tyrosine, D-Htyr(O- alk) is any O-alkylated derivative of α-D-homotyrosine, D-2-Pal is α- D-β-(2-pyridyl)alanine, D-3-Pal is α-D-β-(3-pyridyl)alanine, D-4-Pal is α-D-β-(4-pyridyl)alanine, D-Bip is α-D-β-(4-bi-phenylyl)alanine, D-Bpa is α-D-(4-benzoyl)phenylalanine, D-Dht is α-D-dihydrotryptophan, D- Tha is α-D-β-(2-thienyl)alanine, D-Bta is α-D-β-(3- benzothienyl)alanine, D-1-Nal is α-D-β-(1-napththyl)alanine, D-2-Nal is α-D-β-(2-napththyl)alanine and D-2-Qal is α-D-β-(2- quinolyl)alanine.

1 , 2 or more of any remaining, unspecified amino acid residues in the amyloid-binding peptide sequence may also be each independently selected from, but not limited to, the group consisting of:

D-Abu, D-Nva, D-NIe, D-Aoc, D-Npg, D-lpg, D-Ser(O-alk), D-Hser(O- alk), D-Cys(S-alk) and D-Hcys(S-alk); wherein:

D-Abu is α-D-aminobutyric acid, D-Nva is α-D-norvaline, D-NIe is α- D-norleucine, D-Aoc is α-D-aminooctanoic acid, D-Npg is α-D- neopentylglycine, D-lpg is α-D-isopentylglycine, D-Ser(O-alk) is any O-alkylated derivative of α-D-serine, D-Hser(O-alk) is any O-alkylated derivative of α-D-homoserine, D-Cys(S-alk) is any S-alkylated derivative of α-D-cysteine and D-Hcys(S-alk) is any S-alkylated derivative of α-D-homocysteine.

More specifically, 1 , 2 or more of any remaining, unspecified amino acid residues in the amyloid-binding peptide sequence may be each independently selected from, but not limited to, the group consisting of:

Aib, Deg, Dpg, Ac5c and Acδc; wherein:

Aib is α-aminoisobutyric acid, Deg is α,α-diethylglycine, Dpg is α,α- dipropylglycine, Ac5c is α-aminocyclopentanoic acid and Ac6c is α- aminocyclohexanoic acid; or

D-ldc, D-Oic, D-Hpro, D-Thz and D-Tic; wherein:

D-ldc is α-D-indoline-2-carboxylic acid, D-Oic is α-D- octahydroindoline-2-carboxylic acid, D-Hpro is α-D-homoproline or α- D-pipecolic acid, D-Thz is α-D-thiazolidine-4-carboxylic acid and D- Tic is α-D-tetrahydroisoquinoline-3-carboxylic acid. Furthermore, 1 , 2 or more of any remaining, unspecified amino acid residues in the amyloid-binding peptide sequence may be an α-D-amino acid residues having natural amino acid side chains.

When 1, 2 or more of any remaining, unspecified amino acid residues in the amyloid-binding peptide sequence are α-D-amino acid residues having natural amino acid side chains they may be selected from, but are not limited to, the group consisting of:

D-Leu, D-Pro, D-Phe, D-Met, D-Tyr and D-Trp; wherein:

D-Leu is α-D-leucine, D-Pro is α-D-proline, D-Phe is α-D- phenylalanine, D-Met is α-D-methionine, D-Tyr is α-D-tyrosine and D-

Trp is α-D-tryptophan.

2.14. Peptide backbone modifications

The present invention also provides chemical compounds or compositions, wherein any 1 , 2 or more amide groups in the peptide backbone of the amyloid-binding peptide sequence may be replaced by an amide substitute.

When any 1 , 2 or more amide groups in the peptide backbone of the amyloid-binding peptide sequence are replaced by an amide substitute, the amide substitute can be independently selected from, but is not limited to, the group consisting of:

(a) an N-substituted amide group, [CON(R ^A )];

(b) a thioamide group, [CSNH], or N-substituted thioamide group, [CSN(R ^A )];

(c) a sulphonamide group, [SO ₂ NH], or N-substituted sulphonamide group, [SO ₂ N(R ^A )]; and

(d) [COCH ₂ ] (ketone), [COO] (ester), [CSO], [COS] (thioester) or [CSS] (dithioester);

wherein R ^A is selected from the group consisting of: any alkyl group, methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, benzyl, or any other alkyl or arylalkyl group.

Furthermore, any 1, 2, 3, 4 or more amino acid residues or amide groups in the peptide backbone of the amyloid-binding peptide sequence may be N- methylated or otherwise N-alkylated.

When any 1 , 2, 3, 4 or more amino acid residues or amide groups in the peptide backbone of the amyloid-binding peptide sequence are N- methylated or otherwise N-alkylated, they can be independently selected from the group consisting of, but not limited to:

D-mVal, D-mlle, D-allo-mlle, D-mTϊe, D-mThr(O-alk), D-allo-mThr(O- alk), D-mPen(S-alk), D-mCpg, D-mChg, D-mlng, D-mPhg, D-mCpa, D-mCha, D-mPhe(x), D-mHphe, D-mTyr(O-a!k), D-1-mNal, D-2-mNal, D-mAbu, D-mNva, D-mNle, D-mNpg, D-mLeu, D-mPhe, D-mMet, D- mTyr and D-mTrp; wherein:

D-mVal is N-methyl-α-D-valine, D-mlle is N-methyl-α-D-isoleucine, D- allo-mlle is N-methyl-α-D-allo-isoleucine, D-mTle is N-methyl-α-D- tert-leucine, D-mThr(O-alk) is any O-alkylated derivative of N-methyl- α-D-threonine, D-allo-mThr(O-alk) is any O-alkylated derivative of N- methyl-α-D-allo-threonine, D-mPen(S-alk) is any S-alkylated derivative of N-methyl-α-D-penicillamine, D-mCpg is N-methyl-α-D- cyclopentylglycine, D-mChg is N-methyl-α-D-cyclohexylglycine, D- mlng is N-methyl-α-D-indanylglycine, D-mPhg is N-methyl-α-D- phenylglycine, D-mCpa is N-methyl-α-D-β-(cyclopentyl)alanine, D- mCha is N-methyl-α-D-β-(cyclohexyl)alanine, D-mPhe(x) is any substituted derivative of N-methyl-α-D-phenylalanine, D-mHphe is N- methyl-α-D-homophenylalanine, D-mTyr(O-alk) is any O-alkylated derivative of N-methyl-α-D-tyrosine, D-1-mNal is N-methyl-α-D-β-(1- napththyl)alanine, D-2-mNal is N-methyl-α-D-β-(2-napththyl)alanine,

D-mAbu is N-methyl-α-D-aminobutyric acid, D-mNva is N-methyl-α-D- norvaline, D-mNle is N-methyl-α-D-norleucine, D-mNpg is N-methyl- α-D-neopentylglycine, D-mLeu is N-methyl-α-D-leucine, D-mPhe is N- methyl-α-D-phenylalanine, D-mMet is N-methyl-α-D-methionine, D- mTyr is N-methyl-α-D-tyrosine and D-mTrp is N-methyl-α-D- tryptophan.

The present invention may also relate to chemical compounds or compositions, wherein the amide group connecting X1 to X2 is replaced by an amide substitute. When the amide group connecting X1 to X2 is replaced by an amide substitute, it can be independently selected from, but is not limited to, the group consisting of:

(a) an N-substituted amide group, [CON(R ^A2 )];

(b) a thioamide group, [CSNH], or N-substituted thioamide group, [CSN(R ^A2 )];

(c) a sulphonamide group, [SO ₂ NH], or N-substituted sulphonamide group, [SO ₂ N(R ^A? )]; and

(d) [COCH ₂ ] (ketone), [COO] (ester), [CSO], [COS] (thioester) or [CSS] (dithioester); wherein R ^A2 is selected from the group consisting of: any aikyl group, methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, benzyl, or any other alkyl or arylalkyl group.

Furthermore, X2 or the amide group connecting X1 to X2 may be N- methylated or otherwise N-alkylated. X2 can be selected from the group consisting of:

D-mVal, D-mlle, D-allo-mlle, D-mTle, D-mThr(O-alk), D-allo-mThr(O- alk), D-mPen(S-alk), D-mCpg, D-mChg, D-mlng, D-mPhg, D-mCpa, D-mCha, D-mPhe(x), D-mHphe, D-mTyr(O-alk), D-1-mNal, D-2-mNal, D-mAbu, D-mNva, D-mNIe, D-mNpg, D-mLeu, D-mPhe, D-mMet, D- mTyr and D-mTrp; wherein:

D-mVal is N-methyl-α-D-valine, D-mlle is N-methyl-α-D-isoleucine, D- allo-mlle is N-methyl-α-D-allo-isoleucine, D-mTle is N-methyl-α-D- fert-leucine, D-mThr(O-alk) is any O-alkylated derivative of N-methyl- α-D-threonine, D-allo-mThr(O-alk) is any O-alkylated derivative of N- methyl-α-D-allo-threonine, D-mPen(S-alk) is any S-alkylated derivative of N-methyl-α-D-penicillamine, D-mCpg is N-methyl-α-D- cyclopentylglycine, D-mChg is N-methyl-α-D-cyclohexylglycine, D- mlng is N-methyl-α-D-indanylglycine, D-mPhg is N-methyl-α-D- phenylglycine, D-mCpa is N-methyl-α-D-β-(cyclopentyl)alanine, D- mCha is N-methyl-α-D-β-(cyclohexyl)alanine, D-mPhe(x) is any substituted derivative of N-methyl-α-D-phenylalanine, D-mHphe is N- methyl-α-D-homophenylalanine, D-mTyr(O-alk) is any O-alkylated derivative of N-methyl-α-D-tyrosine, D-1-mNal is N-methyl-α-D-β-(1- napththyl)alanine, D-2-mNal is N-methyl-α-D-β-(2-napththyl)alanine,

D-mAbu is N-methyl-α-D-aminobutyric acid, D-mNva is N-methyl-α-D- norvaline, D-mNIe is N-methyl-α-D-norleucine, D-mNpg is N-methyl- α-D-neopentylglycine, D-mLeu is N-methyl-α-D-leucine, D-mPhe is N- methyl-α-D-phenylalanine, D-mMet is N-methyl-α-D-methionine, D- mTyr is N-methyl-α-D-tyrosine and D-mTrp is N-methyl-α-D- tryptophan.

The present invention may also relate to chemical compounds or compositions in which the amide group connecting X2 to X3 is replaced by an amide substitute. When the amide group connecting X2 to X3 is replaced by an amide substitute, it can be independently selected from, but is not limited to, the group consisting of:

(a) an N-substituted amide group, [CON(R* ³ )];

(b) a thioamide group, [CSNH], or N-substituted thioamide group, [CSN(R ^A3 )];

(c) a sulphonamide group, [SO ₂ NH], or N-substituted sulphonamide group, [SO ₂ N(R")]; and

(d) [COCH ₂ ] (ketone), [COO] (ester), [CSO], [COS] (thioester) or [CSS] (dithioester); wherein R ^A3 is selected from the group consisting of: any alkyl group, methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, benzyl, or any other alkyl or arylalkyl group.

Furthermore, X3 or the amide group connecting X2 to X3 may be N- methylated or otherwise N-alkylated. X3 can be selected from the group consisting of:

D-mVal, D-mlle, D-allo-mlle, D-mTle, D-mThr(O-alk), D-allo-mThr(0- alk), D-mPen(S-alk), D-mCpg, D-mChg, D-mlng, D-mPhg, D-mCpa, D-mCha, D-mPhe(x), D-mHphe, D-mTyr(O-alk), D-1-mNal, D-2-mNal, D-mAbu, D-mNva, D-mNIe, D-mNpg, D-mLeu, D-mPhe, D-mMet, D- mTyr and D-mTrp; wherein:

D-mVal is N-methyl-α-D-valine, D-mlle is N-methyl-α-D-isoleucine, D- allo-mlle is N-methyl-α-D-allo-isoleucine, D-mTle is N-methyl-α-D- ferf-leucine, D-mThr(O-alk) is any O-alkylated derivative of N-methyl- α-D-threonine, D-allo-mThr(O-alk) is any O-alkylated derivative of N- methyl-α-D-allo-threonine, D-mPen(S-alk) is any S-alkylated derivative of N-methyl-α-D-penicillamine, D-mCpg is N-methyl-α-D- cyclopentylglycine, D-mChg is N-methyl-α-D-cyclohexylglycine, D- mlng is N-methyl-α-D-indanylglycine, D-mPhg is N-methyl-α-D- phenylglycine, D-mCpa is N-methyl-α-D-β-(cyclopentyl)alanine, D- mCha is N-methyl-α-D-β-(cyclohexyl)alanine, D-mPhe(x) is any substituted derivative of N-methyl-α-D-phenylalanine, D-mHphe is N- methyl-α-D-homophenylalanine, D-mTyr(O-alk) is any O-alkylated derivative of N-methyl-α-D-tyrosine, D-1-mNal is N-methyl-α-D-β-(1- napththyl)alanine, D-2-mNal is N-methyl-α-D-β-(2-napththyl)alanine,

D-mAbu is N-methyl-α-D-aminobutyric acid, D-mNva is N-methyl-α-D- norvaline, D-mNIe is N-methyl-α-D-norleucine, D-mNpg is N-methyl- α-D-neopentylglycine, D-mLeu is N-methyl-α-D-leucine, D-mPhe is N- methyl-α-D-phenylalanine, D-mMet is N-methyl-α-D-methionine, D- mTyr is N-methyl-α-D-tyrosine and D-mTrp is N-methyl-α-D- tryptophan.

The present invention may also relate to chemical compounds or compositions, wherein the amide group connecting X3 to X4 is replaced by an amide substitute. When the amide group connecting X3 to X4 is replaced by an amide substitute, it can be independently selected from, but is not limited to, the group consisting of:

(a) an N-substituted amide group, [CON(R ^A4 )];

(b) a thioamide group, [CSNH], or N-substituted thioamide group, [CSN(R ^A4 )];

(c) a sulphonamide group, [SO ₂ NH], or N-substituted sulphonamide group, [SO ₂ N(R ^Aϊ )]; and

(d) [COCH ₂ ] (ketone), [COO] (ester), [CSO], [COS] (thioester) or [CSS] (dithioester); wherein R ^M is selected from the group consisting of: any alkyl group, methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, benzyl, or any other alkyl or arylalkyl group.

X4 or the amide group connecting X3 to X4 may be N-methylated or otherwise N-alkylated. X4 can be selected from the group consisting of:

D-mVal, D-mlle, D-allo-mlle, D-mTle, D-mThr(O-alk), D-allo-mThr(O- alk), D-mPen(S-alk), D-mCpg, D-mChg, D-mlng, D-mPhg, D-mCpa, D-mCha, D-mPhe(x), D-mHphe, D-mTyr(O-alk), D-1-mNal, D-2-mNal, D-mAbu, D-mNva, D-mNIe, D-mNpg, D-mLeu, D-mPhe, D-mMet, D- mTyr and D-mTrp; wherein:

D-mVal is N-methyl-α-D-valine, D-mlle is N-methyl-α-D-isoleucine, D- allo-mlle is N-methyl-α-D-allo-isoleucine, D-mTle is N-methyl-α-D- terf-leucine, D-mThr(O-alk) is any O-alkylated derivative of N-methyl- α-D-threonine, D-allo-mThr(O-alk) is any O-alkylated derivative of N- methyl-α-D-allo-threonine, D-mPen(S-alk) is any S-alkylated derivative of N-methyl-α-D-penicillamine, D-mCpg is N-methyl-α-D- cyclopentylglycine, D-mChg is N-methyl-α-D-cyclohexylglycine, D- mlng is N-methyl-α-D-indanylglycine, D-mPhg is N-methyl-α-D- phenylglycine, D-mCpa is N-methyl-α-D-β-(cyclopentyl)alanine, D- mCha is N-methyl-α-D-β-(cyclohexyl)alanine, D-mPhe(x) is any substituted derivative of N-methyl-α-D-phenylalanine, D-mHphe is N- methyl-α-D-homophenylalanine, D-mTyr(O-alk) is any O-alkylated derivative of N-methyl-α-D-tyrosine, D-1-mNal is N-methyl-α-D-β-(1- napththyl)alanine, D-2-mNal is N-methyl-α-D-β-(2-napththyl)alanine,

D-mAbu is N-methyl-α-D-aminobutyric acid, D-mNva is N-methyl-α-D- norvaline, D-mNIe is N-methyl-α-D-norleucine, D-mNpg is N-methyl- α-D-neopentylglycine, D-mLeu is N-methyl-α-D-leucine, D-mPhe is N- methyl-α-D-phenylalanine, D-mMet is N-methyl-α-D-methionine, D- mTyr is N-methyl-α-D-tyrosine and D-mTrp is N-methyl-α-D- tryptophan.

The present invention may also relate to chemical compounds or compositions wherein the amide group connecting X4 to X5 is replaced by an amide substitute. When the amide group connecting X4 to X5 is replaced by an amide substitute, it can be independently selected from, but is not limited to, the group consisting of:

(a) an N-substituted amide group, [CON(R ^A5 )];

(b) a thioamide group, [CSNH], or N-substituted thioamide group, [CSN(R ^A5 )];

(c) a sulphonamide group, [SO ₂ NH], or N-substituted sulphonamide group, [SO ₂ N(FO]; and

(d) [COCH ₂ ] (ketone), [COO] (ester), [CSO], [COS] (thioester) or [CSS] (dithioester); wherein R ^A5 is selected from the group consisting of: any alkyl group, methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, benzyl, or any other alkyl or arylalkyl group.

X5 or the amide group connecting X4 to X5 may be N-methylated or otherwise N-alkylated. X5 can be selected from the group consisting of:

D-mVal, D-mlle, D-allo-mlle, D-mTle, D-mThr(O-alk), D-a!lo-mThr(O- alk), D-mPen(S-alk), D-mCpg, D-mChg, D-mlng, D-mPhg, D-mCpa, D-mCha, D-mPhe(x), D-mHphe, D-mTyr(O-alk), D-1-mNal, D-2-mNal, D-mAbu, D-mNva, D-mNIe, D-mNpg, D-mLeu, D-mPhe, D-mMet, D- mTyr and D-mTrp; wherein:

D-mVal is N-methyl-α-D-valine, D-mlle is N-methyl-α-D-isoleucine, D- allo-mlle is N-methyl-α-D-allό-isoleucine, D-mTle is N-methyl-α-D- terf-leucine, D-mThr(O-alk) is any O-alkylated derivative of N-methyl- α-D-threonine, D-allo-mThr(O-alk) is any O-alkylated derivative of N- methyl-α-D-allo-threonine, D-mPen(S-alk) is any S-alkylated derivative of N-methyl-α-D-penicillamine, D-mCpg is N-methyl-α-D- cyclopentylglycine, D-mChg is N-methyl-α-D-cyclohexylglycine, D- mlng is N-methyl-α-D-indanylglycine, D-mPhg is N-methyl-α-D- phenylglycine, D-mCpa is N-methyl-α-D-β-(cyclopentyl)alanine, D- mCha is N-methyl-α-D-β-(cyclohexyl)alanine, D-mPhe(x) is any substituted derivative of N-methyl-α-D-phenylalanine, D-mHphe is N- methyl-α-D-homophenylalanine, D-mTyr(O-alk) is any O-alkylated derivative of N-methyl-α-D-tyrosine, D-1-mNal is N-methyl-α-D-β-(1- napththyl)alanine, D-2-mNal is N-methyl-α-D-β-(2-napththyl)alanine,

D-mAbu is N-methyl-α-D-aminobutyric acid, D-mNva is N-methyl-α-D- norvaline, D-mNIe is N-methyl-α-D-norleucine, D-mNpg is N-methyl- α-D-neopentylglycine, D-mLeu is N-methyl-α-D-leucine, D-mPhe is N- methyl-α-D-phenylalanine, D-mMet is N-methyl-α-D-methionine, D- mTyr is N-methyl-α-D-tyrosine and D-mTrp is N-methyl-α-D- tryptophan.

Preferably, the chemical compounds or compositions of the present invention comprise amino acid residues wherein:

X2 and X4 are each N-methylated or otherwise N-alkylated; or X1 , X3 and X5 are each N-methylated or otherwise N-alkylated; or

X1 and X5 are each N-methylated or otherwise N-alkylated; or X1 and X3 are each N-methylated or otherwise N-alkylated; or X3 and X5 are each N-methylated or otherwise N-alkylated; or

only X5 is N-methylated or otherwise N-alkylated, while every other amino acid residue in the amyloid-binding peptide sequence remains unalkylated.

Where appropriate, the chemical compounds or compositions of the present invention may comprise combinations of the above, preferred, amino acid residue combinations.

2.15. Specific examples of N-methylated peptide sequences

In another aspect, the present invention provides chemical compounds or compositions wherein the amyloid-binding peptide sequence may comprise or consist of an N-methylated, α-D-isoleucine~containing amino acid sequence.

When the amyloid-binding peptide sequence comprises or consists of an N- methylated, α-D-isoleucine-containing amino acid sequence, it can be selected from, but is not limited to, the group consisting of: (a) a 3-residue amino acid sequence selected from the group consisting of:

[(D-lle)-(D-lleHD-mlle)], [(D-lle)-(D-lle)-(D-mVal)], [(D-IIe)-(D-IIe)-(D- mLeu)], [(D-lie)-(D-ValHD-mLeu)], [(D-lle)-(D-allo-lle)-(D-mLeu)], [(D- lle)-(D-LeuHD-mLeu)], [(D-lleHD-TleHD-mLeu)], [(D-VaI)-(D-IIe)-(D- mLeu)], [(D-allo-lle)-(D-lle)-(D-mLeu)], [(D-LeuMD-lle)-(D-mLeu)] and

[(D-Tle)-(D-lle)-(D-mLeu)];

(b) a 4-residue amino acid sequence selected from the group consisting of:

[(D-lleHD-lleHD-lleHD-mLeu)] ₎ [(D-lle)-(D-lle)-(D-lle)-(D-mVal)], [(D- lle)-(D-lle)-(D-lle)-(D-mlle)], [(D-Val)-(D-lle)-(D-lle)-(D-mLeu)], [(D- allo-lle)-(D-lle)-(D-lleHD-mLeu)], [(D-Leu)-(D-lle)-(D-lle)-(D-mLeu)], [(D-Tle)-(D-lle)-(D-lleHD-mLeu)], [(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)], [(D-allo-lle)-(D-lle)-(D-Leu)-(D-mLeu)] and [(D-TIe)-(D-IIe)-(D-LeU)-(D- mLeu)]; and (c) a 5-residue amino acid sequence selected from the group consisting of:

[(D-lleHD-lleHD-lleHD-lle)-(D-mLeu)], [(D-IIe)-(D-IIe)-(D-IIeHD-IIe)- (D-mVal)], [(D-IIe)-(D-IIeMD-IIe)-(D-IIe)-(D-ITiIIe)], [(D-IIe)-(D-VaI)-(D- HeMD-lle)-(D-mLeu)], [(D-lleMD-allo-lle)-(D-lle)-(D-lle)-(D-mLeu)], [(D-lleHD-LeuHD-lle)-(D-lle)-(D-mLeu)], [(D-IIe)-(D-TIe)-(D-IIe)-(D-

He)-(D-mLeu)], [(D-lle)-(D-Val)-(D-lle)-(D-LeuHD-mLeu)], [(D-IIe)-(D- allo-lle)-(D-lle)-(D-Leu)-(D-mLeu)], [(D-IIe)-(D-TIe)-(D-IIe)-(D-LeU)-(D- mLeu)]; wherein: D-VaI is α-D-valine, D-IIe is α-D-isoleucine, D-allo-lle is α-D-allo- isoleucine, D-Leu is α-D-leucine, D-TIe is α-D-fe/f-leucine, D-mVal is N-methyl-α-D-valine, D-mlle is N-methyl-α-D-isoleucine and D-mLeu is N-methyl-α-D-leucine.

The amyloid-binding peptide sequence of the chemical compounds or compositions of the present invention may comprise or consist of an N- methylated, D-cyclohexylglycine-containing amino acid sequence.

When the amyloid-binding peptide sequence comprises or consists of an N- methylated, D-cyclohexylglycine-containing amino acid, it can be selected from, but is not limited to, the group consisting of:

(a) a 3-residue amino acid sequence selected from the group consisting of:

[(D-Chg)-(D-ChgHD-mChg)], [(D-ChgHD-Chg)-(D-mVal)], [(D-Chg)- (D-Chg)-(D-mlle)], [(D-Chg)-(D-Chg)-(D-ml_eu)], [(D-Val)-(D-Chg)-(D- mLeu)], [(D-lle)-(D-Chg)-(D-mLeu)], [(D-Leu)-(D-Chg)-(D-mLeu)], [(D- Tle)-(D-Chg)-(D-mLeu)], [(D-Cpg)-(D-Chg)-(D-mLeu)], [(D-lng)-(D- Chg)-(D-mLeu)], [(D-Chg)-(D-Val)-(D-ml_eu)], [(D-Chg)-(D-I Ie)-(D- mLeu)], [(D-ChgMD-Leu)-(D-mLeu)], [(D-Chg)-(D-Tle)-(D-mLeu)], [(D- Chg)-(D-Cpg)-(D-mLeu)] and [(D-Chg)-(D-!ng)-(D-mLeu)];

(b) a 4-residue amino acid sequence selected from the group consisting of:

[(D-Chg)-(D-Chg)-(D-Chg)-(D-mChg)], [(D-Chg)-(D-Chg)-(D-Chg)-(D- mVal)], [(D-ChgHD-ChgHD-ChgHD-mlle)], [(D-Chg)-(D-ChgHD- Chg)-(D-mLeu)], [(D-Val)-(D-Chg)-(D-Chg)-(D-mLeu)], [(D-IIe)-(D-

ChgHD-Chg)-(D-mLeu)], [(D-allo-lle)-(D-Chg)-(D-Chg)-(D-mLeu)], [(D-Leu)-(D-Chg)-(D-Chg)-(D-mLeu)], [(D-Tle)-(D-Chg)-(D-Chg)-(D- mLeu)], [(D-Phe)-(D-Chg)-(D-Chg)-(D-mLeu)], [(D-Tyr)-(D-Chg)-(D- Chg)-(D-mLeu)], [(D-Cpg)-(D-ChgHD-Chg)-(D-mLeu)] and [(D-Ing)- (D-Chg)-(D-Chg)-(D-mLeu)]; and

(c) a 5-residue amino acid sequence selected from the group consisting of:

[(D-ChgHD-ChgHD-Chg)-(D-Chg)-(D-mChg)], [(D-ChgHD-Chg)-(D- Chg)-(D-Chg)-(D-mVal)], [(D-Chg)-(D-Chg)-(D-Chg)-(D-Chg)-(D- mile)], [(D-Chg)-(D-Chg)-(D-Chg)-(D-Chg)-(D-mLeu)], [(D-Chg)-(D-

Val)-(D-Chg)-(D-Chg)-(D-mLeu)], [(D-Chg)-(D-lle)-(D-Chg)-(D-Chg)- (D-mLeu)], [(D-Chg)-(D-allo-lleHD-Chg)-(D-ChgHD-mLeu)], [(D- Chg)-(D-Leu)-(D-Chg)-(D-Chg)-(D-mLeu)], [(D-Chg)-(D-Tle)-(D-Chg)- (D-Chg)-(D-mLeu)], [(D-Chg)-(D-Phe)-(D-Chg)-(D-Chg)-(D-mLeu)], [(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)], [(D-Chg)-(D-Cpg)-(D-

ChgHD-Chg)-(D-mLeu)] and [(D-Chg)-(D-lng)-(D-Chg)-(D-Chg)-(D- mLeu)]; wherein:

D-VaI is α-D-valine, D-IIe is α-D-isoleucine, D-allo-lle is α-D-allo- isoleucine, D-Leu is α-D-leucine, D-TIe is α-D-fe/f-leucine, D-Phe is α-D-phenylalanine, D-Tyr is α-D-Tyrosine, D-Chg is α-D- cyclohexylglycine, D-Cpg is α-D-cyclopentylglycine, D-lng is α-D- indanyl-glycine, D-mVal is N-methyl-α-D-valine, D-mlle is N-methyl-α- D-isoleucine and D-mLeu is N-methyl-α-D-leucine.

2.16. N-terminal modifications

A further aspect of the present invention relates to chemical compounds or compositions wherein the amyloid-binding peptide sequence may form part of an extended peptide, wherein an N-terminal peptide sequence consisting of 1 , 2, 3, 4 or more additional amino acid residues is attached to the N- terminal end of the amyloid-binding peptide sequence.

The amyloid-binding peptide sequence may have an unmodified N-terminal amino group. Alternatively, the amyloid-binding peptide sequence may have a hydrogen atom in place of an N-terminal amino group. The amyloid-binding peptide sequence may have a modified N-terminal amino group.

When the N-terminal amino group is modified, it may be substituted with one or two substituents. The modified N-terminal amino group can be selected from, but is not limited to, the group consisting of (R )NH and (R ^N2 )(R ^N3 )N, wherein:

(a) R ^N1 , R ^N2 and R ^N3 are each independently selected from the group consisting of: i. any group comprising 1, 2, 3, 4, 5, 6, 7, 8 or more carbon atoms in total, no more than 3, 2, 1 or 0 hydrogen bond donors, no more than 3, 2, 1 or 0 hydrogen bond acceptors, and no more than 6, 5, 4, 3, 2, 1 or 0 rotatable bonds; ii. any aliphatic group selected from the group consisting of: alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, 3-pentyl, neopentyl, isopentyl, fert-pentyl, hexyl, heptyl, octyl, alkylaminoalkyl, alkylaminomethyl, alkylaminoethyl, alkylaminopropyl, dialkylaminoalkyl, dialkylaminomethyl, dialkylaminoethyl, dialkylaminopropyl, alkoxyalkyl, alkoxymethyl, alkoxyethyl, alkoxypropyl, alkylthioalkyl, alkylthiomethyl, alkylthioethyl and alkylthiopropyl; where the said selected aliphatic group is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents; iii. an aryl, arylalkyl, arylmethyl, arylethyl, arylaminoalkyl, aryloxyalkyl, arylthioalkyl or other aromatic group comprising an aromatic ring that is independently selected from the group consisting of: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, indazolyl, benzotriazolyl, naphthyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl and quinoxalinyl; wherein the selected aromatic ring is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents; iv. any group comprising a cyclic aliphatic ring that is selected from the group consisting of: cycloalkyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thioxetanyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, cyclohexyl, cycloheptyl, cyclooctyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,

piperazinyl, dioxanyl, dithianyl, oxathianyl, morpholinyl, thiomorpholinyl, indanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, tetrahydronaphthyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzodioxanyl, benzodithianyl, benzoxathianyl, benzomorpholinyl, benzothiomorpholinyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl, bisnoradamantyl, twistbrendanyl and twistanyl; wherein the selected cyclic aliphatic ring is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents; and v. CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CI, CFCI ₂ , CCI ₃ , CHCI ₂ , CH ₂ CI, CH ₃ ,

(R ^N4 )CH ₂ , (R ^N5 )CH ₂ CH ₂ , (R ^N6 )CH ₂ CH ₂ CH ₂ , (R ^N7 )CO, (R ^N8 )CH ₂ CO, (R ^N9 )CH ₂ CH ₂ CO, (R ^N10 )CH ₂ CH ₂ CH ₂ CO,

(R ^N11 )SO ₂ , (R ¹ ^)CH ₂ SO ₂ , (R ^N13 )CH ₂ CH ₂ SO ₂ or (R ^N14 )CH ₂ CH ₂ CH ₂ SO ₂ ; and

(b) R ^N4 , R ^N5 , R ^N6 , R ^N7 , R ^m , R ^m , R ^mo , R ^N1 \ R ^N12 , R ^N13 and R ^N14 are each independently selected from the group consisting of: i. any group comprising 1 , 2, 3, 4, 5, 6, 7, 8 or more carbon atoms in total, no more than 3, 2, 1 or 0 hydrogen bond donors, no more than 3, 2, 1 or 0 hydrogen bond acceptors, and no more than 6, 5, 4, 3, 2, 1 or 0 rotatable bonds; ii. any aliphatic group selected from the group consisting of: alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, 3-pentyl, neopentyl, isopentyl, tert-pentyl, hexyl, heptyl, octyl, alkylaminoalkyl, alkylaminomethyl, alkylaminoethyl, alkylaminopropyl, dialkylaminoalkyl, dialkylaminomethyl, dialkylaminoethyl, dialkylaminopropyl, alkoxyalkyl, alkoxymethyl, alkoxyethyl, alkoxypropyl, alkylthioalkyl, alkylthiomethyl, alkylthioethyl and alkylthiopropyl; where the said selected aliphatic group is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents; iii. an aryl, arylalkyl, arylmethyl, arylethyl, arylaminoalkyl, aryloxyalkyl, arylthioalkyl or other aromatic group comprising an aromatic ring that is independently selected from the group consisting of: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, indazolyl, benzotriazolyl, naphthyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl and quinoxalinyl; wherein the selected aromatic ring is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents; iv. any group comprising a cyclic aliphatic ring that is selected from the group consisting of: cycloalkyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thioxetanyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, cyclohexyl, cycloheptyl,

cyclooctyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, oxathianyl, morpholinyl, thiomorpholinyl, indanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, tetrahydronaphthyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzodioxanyl, benzodithianyl, benzoxathianyl, benzomorpholinyl, benzothiomorpholinyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl, bisnoradamantyl, twistbrendanyl and twistanyl; wherein the selected cyclic aliphatic ring is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents; and v. H, F, Cl, Br, I ₁ CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CI, CFCI ₂ , CCI ₃ , CHCI ₂ , CH ₂ Cl Or CN.

Furthmore, the amyloid-binding peptide sequence may have a modified N- terminal amino group selected from the group consisting of (R ^N1 )NH and (R ^N2 )(R ^N3 )N, wherein R ^N \ R ^N2 and R ^m are independently selected from, but not limited to, the group consisting of: (a) methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ferf-butyl, or any other alkyl group; and

(b) (R ^N8 )CH ₂ CO, wherein R ^m is selected from the group consisting of: i. H ₁ methyl, ethyl, propyl, isopropyl, butyl, isobutyl, f-butyl, or any other alkyl group; ii. any aromatic ring selected from the group consisting of: phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl; wherein the aromatic ring is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents; and iii. a cyclic aliphatic ring selected from the group consisting of: cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, indanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, dithianyl, piperazinyl, oxathianyl, morpholinyl, thiomorpholinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, benzomorpholinyl, benzothiomorpholinyl, benzodioxanyl, benzodithianyl and benzoxathianyl; wherein the selected cyclic aliphatic ring is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents.

Further amyloid-binding peptide sequences having a modified N-terminal amino group may be selected from the group consisting of:

(a) methylamino, ethylamino, propylamine) or isopropylamino;

(b) dimethylamino, diethylamino, dipropylamino or diisopropylamino;

(c) acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or 4- methylpiperazin-1-yl; and (d) (i-pyrrolidinyl)acetylamino, (i-piperidinyl)acetylamino, (4- morpholinyl)acetylamino or (4-methylpiperazin-1-yl)acetylamino.

The modified N-terminal amino group may also be selected from (3- hydrσxyM -piperidinyl)acetylamino, (4-hydroxy-1 -piperidinyl)acetylamino or (3-hydroxy-1-pyrrolidinyl)acetylamino. Modication of the N-terminus is often preferred because it can assist in association of the amyloid-binding peptide sequence with a target amyloid- forming protein or peptide.

2.17. C-terminal modifications The present invention may also relate to chemical compounds or compositions, wherein the amyloid-binding peptide sequence forms part of an extended peptide wherein a C-terminal peptide sequence consisting of 1 , 2, 3, 4 or more additional amino acid residues is attached to the C- termihal end of the amyloid-binding peptide sequence. The amyloid-binding peptide sequence may have an unmodified C-terminal carboxyl or amide group. Alternatively, the amyloid-binding peptide sequence has a hydrogen atom in place of a C-terminal carboxyl or amide group.

The amyloid-binding peptide sequence may have a modified C-terminal carboxyl or amide group.

When the C-terminal carboxyl or amide group is modified, it may be substituted with one or two substituents. The modified C-terminal carboxyl or amide group can be selected from, but is not limited to, the group consisting of COO(R ^C0 ), CONH(R ^C1 ) and CON(R ^C2 )(R ^C3 ), wherein: (a) R ^co , R ^C1 , R ^C2 and R ^C3 are each independently selected from the group consisting of: i. any group comprising 1 , 2, 3, 4, 5, 6, 7, 8 or more carbon atoms in total, no more than 3, 2, 1 or 0 hydrogen bond donors, no more than 3, 2, 1 or 0 hydrogen bond acceptors, and no more than 6, 5, 4, 3, 2, 1 or 0 rotatable bonds; ii. any aliphatic group selected from the group consisting of: alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, 3-pentyl, neopentyl, isopentyl, fe/f-pentyl, hexyl, heptyl, octyl, alkylaminoalkyl, alkylaminomethyl, alkylaminoethyl, alkylaminopropyl, dialkylaminoalkyl, dialkylaminomethyl, dialkylaminoethyl, dialkylaminopropyl, alkoxyalkyl, alkoxymethyl, alkoxyethyl, alkoxypropyl, alkylthioalkyl, alkylthiomethyl, alkylthioethyl and alkylthiopropyl; where the said selected aliphatic group is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents;

iii. an aryl, arylalkyl, arylmethyl, arylethyl, arylaminoalkyl, aryloxyalkyl, arylthioalkyl or other aromatic group comprising an aromatic ring that is independently selected from the group consisting of: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyi, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, indazolyl, benzotriazolyl, naphthyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl and quinoxalinyl; wherein the selected aromatic ring is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents; iv. any group comprising a cyclic aliphatic ring that is selected from the group consisting of: cycloalkyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thioxetanyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, cyclohexyl, cycloheptyl, cyclooctyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, oxathianyl, morpholinyl, thiomorpholinyl, indanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, tetrahydronaphthyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzodioxanyl, benzodithianyl, benzoxathianyl, benzomorpholinyl, benzothiomorpholinyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl, bisnoradamantyl, twistbrendanyl and twistanyl; wherein the selected cyclic aliphatic ring is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents; and v. CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CI, CFCI ₂ , CCI ₃ , CHCI ₂ , CH ₂ CI, CH ₃ ,

CH ₂ (R ⁰⁴ ), CH ₂ CH ₂ (R ⁰⁵ ) or CH ₂ CH ₂ CH ₂ (R ⁰⁶ ); and

(b) R ^C4 , R ⁰⁵ and R ^C6 are each independently selected from the group consisting of: i. any group comprising 1 , 2, 3, 4, 5, 6, 7, 8 or more carbon atoms in total, no more than 3, 2, 1 or 0 hydrogen bond donors, no more than 3, 2, 1 or 0 hydrogen bond acceptors, and no more than 6, 5, 4, 3, 2, 1 or 0 rotatable bonds; ii. any aliphatic group selected from the group consisting of: alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, 3-pentyl, neopentyl, isopentyl, ferf-pentyl, hexyl, heptyl, octyl, alkylaminoalkyl, alkylaminomethyl, alkylaminoethyl, alkylaminopropyl, dialkylaminoalkyl, dialkylaminomethyl, dialkylaminoethyl, dialkylaminopropyl, alkoxyalkyl, alkoxymethyl, alkoxyethyl, alkoxypropyl, alkylthioalkyl, alkylthiomethyl, alkylthioethyl and alkylthiopropyl; where the said selected aliphatic group is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents; iii. an aryl, arylalkyl, arylmethyl, arylethyl, arylaminoalkyl, aryloxyalkyl, arylthioalkyl or other aromatic group comprising an

aromatic ring that is independently selected from the group consisting of: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyi, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, indazolyl, benzotriazolyl, naphthyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl and quinoxalinyl; wherein the selected aromatic ring is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents; iv. any group comprising a cyclic aliphatic ring that is selected from the group consisting of: cycloalkyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thioxetanyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, cyclohexyl, cycloheptyl, cyclooctyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, oxathianyl, morpholinyl, thiomorpholinyl, indanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, tetrahydronaphthyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzodioxanyl, benzodithianyl, benzoxathianyl, benzomorpholinyl, benzothiomorpholinyl, norbomyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl, bisnoradamantyl, twistbrendanyl and twistanyl; wherein the selected cyclic aliphatic ring is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents; and v. H, F, Cl, Br, I ₁ CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CI, CFCI ₂ , CCI ₃ , CHCI ₂ , CH ₂ CI or CN. Furthermore, the amyloid-binding peptide sequence may have a modified

C-terminal carboxyl or amide group selected from the group consisting of COO(R ^C0 ), CONH(R ⁰¹ ) and CON(R ^G2 )(R ^C3 ), wherein R ^co , R ^C1 , R ^C2 and R ^C3 are each independently selected from, but not limited to, the group consisting of: (a) methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ferf-butyl, or any other alkyl group; and

(b) CH ₂ (R ⁰⁴ ), wherein R ^c4 is selected from the group consisting of: i. any aromatic ring selected from the group consisting of: phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyi, isoxazolyl, thiazolyl, isothiazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl; wherein the aromatic ring is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents; and ii. a cyclic aliphatic ring selected from the group consisting of: cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, indanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl,

dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, dithianyl, piperazinyl, oxathianyl, morpholinyl, thiomorpholinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, benzomorpholinyl, benzothiomorpholinyl, benzodioxanyl, benzodithianyl and benzoxathianyl; wherein the selected cyclic aliphatic ring is optionally substituted with 1 , 2, 3, 4, 5, 6 or more substituents.

Further amyloid-binding peptide sequences having a modified C-terminal carboxyl or amide groups may be selected from the group consisting of:

(a) methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl or isopropyloxycarbonyl; (b) methylaminocarbonyl, ethylaminocarbonyl or propylaminocarbonyl;

(c) dimethylaminocarbonyl, diethylaminocarbonyl or dipropylaminocarbonyl; and

(d) (i-pyrrolidinyl)carbonyl, (i-piperidinyl)carbonyl or (4- morpholinyl)carbonyl.

2.18. Analogues, derivatives and substituents

The aforementioned chemical compounds or compositions of the present invention may be replaced by an analogue or derivative of the compound or composition. A suitable analogue or derivative retains all the structural features of the compound or composition which are essential for binding to the target amyloid-forming protein or peptide. Therefore, the present invention relates to chemical compounds or compositions which, when replaced by an analogue or derivative, retain all the structural features of the compound or composition which are essential for binding to the target amyloid-forming protein or peptide.

Suitable analogues or derivatives of the compounds or compositions of the present invention may comprise a β-strand mimetic that is modelled after the amyloid-binding peptide sequence in an extended β-strand conformation. In one aspect of the present invention any 1 , 2, 3, 4, 5, 6 or more hydrogen atoms in the compound or composition may be replaced by substituents.

Substituents which may be used to replace any 1 , 2, 3, 4, 5, 6 or more hydrogen atoms in the chemical compounds or compositions can be independently selected from, but are not limted to, the group consisting of: (a) any group comprising no more than 6, 5, 4, 3, 2, 1 or 0 carbon atoms in total, more than one hydrogen bond donor, no more than 3, 2, 1 or 0 hydrogen bond acceptors, and no more than 5, 4, 3, 2, 1 or 0 rotatable bonds;

(b) methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terf-butyl, pentyl or hexyl;

(c) F, Cl, Br, I ₁ CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CI, CFCI ₂ , CCI ₃ , CHCI ₂ , CH ₂ CI or CN; and

(d) CO(R ^S1 ), CON(R ^S2 )(R ⁸³ ), N(R ^S4 )CO(R ^S5 ), CO ₂ (R ⁵³⁶ ), OCO(R ^S7 ), COS(R ^S8 ), SCO(R ³⁹ ), SO(R ^S1 °), SO ₂ (R ^S11 ), SO ₂ N(R ^S12 )(R ^S13 ), N(R ^S14 )SO ₂ (R ^S15 ), SO ₂ O(R ³¹⁶ ), OSO ₂ (R ³¹⁷ ), N(R ^S18 )(R ^S19 ), O(R ^S20 ),

S(R ⁸²¹ ); wherein R ^S1 , R ^S2 , R ^S3 , R ⁸⁴ , R ^S5 , R ³⁶ , R ^S7 , R ^S8 , R ³⁹ , R ⁸¹⁰ , R ⁸¹¹ , R ³¹² , R ⁸¹³ , R ^su , R ⁸¹⁵ , R ⁸¹⁶ , R ⁸¹⁷ , R ⁸¹⁸ , R ⁸¹⁹ , R ⁸²⁰ and R ³²¹ are each independently selected from the group consisting of: i. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terf-butyl, pentyl or hexyl; and ii. H, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CI, CFCI ₂ , CCI ₃ , CHCI ₂ , CH ₂ CI or CN.

Each hydrogen atom which may be replaced by a substituent, can be independently selected from the group consisting of: (a) a hydrogen atom which is directly attached to an α-nitrogen atom of

X1, X2, X3, X4 or X5;

(b) a hydrogen atom which is directly attached to the α-carbon atom of X1 , X2, X3, X4 or X5;

(c) a hydrogen atom which is directly attached to a carbon, nitrogen, oxygen or sulphur atom in the side chain of X1 , X2, X3, X4 or X5, or in an N- or C-terminal group; and

(d) a hydrogen atom which is directly attached to an aromatic or cyclic aliphatic ring in the side chain of X1 , X2, X3, X4 or X5, or in an N- or C-terminal group. Furthermore, chemical compounds or compositions of the present invention may be replaced by a prodrug which is metabolised, or else transformed, into the original compound in vivo.

2.19. Secondary functional components In another aspect of the present invention, the chemical compounds or compositions may comprise 1 , 2, 3, 4 or more secondary functional components.

The secondary functional components can be independently selected from, but are not limited to, the group consisting of: (a) an atom or group which directly or indirectly enhances the binding affinity of the amyloid-binding peptide sequence for the target amyloid-forming protein or peptide;

(b) an atom or group which enhances the binding specificity or selectivity of the amyloid-binding peptide sequence for the target amyloid- forming protein or peptide;

(c) an atom or group which enhances the overall bioavailability of the compound in vivo;

(d) an atom or group which enhances the absorption of the compound through the gut wall, nasal mucosa, pulmonary epithelium, blood- brain barrier, cell membranes, skin, or other biological membrane or barrier; (e) an atom or group which enhances delivery of the compound to a target organ;

(f) an atom or group which enhances the overall solubility of the compound;

(g) an atom or group which enhances the chemical or biological stability of the compound;

(h) an atom or group which reduces the metabolism or clearance of the compound in vivo;

(i) an atom or group which enables the compound to be traced or detected; and (j) an atom or group which enhances the ability of the compound to inhibit the aggregation or toxicity of the target amyloid-forming protein or peptide.

When the chemical compounds or compositions of the present invention comprise an atom or group that directly or indirectly enhances the binding affinity of the amyloid-binding peptide sequence for the target amyloid- forming protein or peptide, the said atom or group may be selected from the group consisting of:

(a) a group which is essentially derived from or otherwise based on a small organic molecule that binds to amyloid; (b) an additional amino acid residue or peptide sequence which forms a favourable interaction with the target amyloid-forming protein or peptide;

(c) an additional amyloid-binding peptide sequence;

(d) a group derived from a small organic molecule which binds to and recruits a bulky protein molecule; and

(e) an epitope or other group which is recognised by an antibody.

When the chemical compounds or compositions of the present invention comprise an atom or group which enhances the binding specificity or selectivity of the amyloid-binding peptide sequence for the target amyloid- forming protein or peptide, the said atom or group may be selected from the group consisting of:

(a) a group that forms a specific interaction with the target amyloid- forming protein or peptide, or which otherwise binds specifically or selectively to the target amyloid-forming protein or peptide; and (b) an additional amino acid residue or peptide sequence which forms a specific interaction with the target amyloid-forming protein or peptide, or which otherwise binds specifically or selectively to the target amyloid-forming protein or peptide.

Furthermore, the chemical compounds or compositions of the present invention may comprise an atom or group which enhance the overall bioavailability of the compound in vivo.

When the chemical compounds or compositions of the present invention comprise an atom or group which enhances the absorption of the compound through the gut wall, nasal mucosa, pulmonary epithelium, blood-brain barrier, cell membranes, skin, or other biological membrane or barrier, the said atom or group may be selected from the group consisting of: (a) a membrane-translocating peptide sequence or other group;

(b) a peptide sequence or other group which has 1 , 2, 3, 4, 5 or more positive charges; and

(c) a peptide sequence or other group which is carried by a specific transporter protein. When the chemical compounds or compositions of the present invention comprise an atom or group which enhances delivery of the compound to a target organ, the said atom or group may be selected from the group consisting of:

(a) a peptide sequence or other group which binds to an organ-specific receptor; and

(b) a peptide sequence or other group which is carried by an organ- specific transporter protein.

When, the chemical compounds or compositions of the present invention comprise an atom or group which enhances the solubility of the compound, the said atom or group may be selected from the group consisting of:

(a) a group which hinders self-association of the compound in both water and organic solvents;

(b) a group which is charged in water at pH 7.5, and essentially uncharged in organic solvents; (c) a group comprising a nitrogen atom which has a pKa value between

7.5 and 9.0; and

(d) a group comprising a quaternary ammonium ion.

When, the chemical compounds or compositions of the present invention comprise an atom or group which enhances the chemical or biological stability of the compound, the said atom or group may be selected from the group consisting of:

(a) a group which inhibits oxidation of the compound; and

(b) a group which inhibits hydrolysis of the compound.

When, the chemical compounds or compositions of the present invention comprise an atom or group which reduces the metabolism or clearance of the compound in vivo, the said atom or group may be selected from the group consisting of:

(a) a group which inhibits oxidation of the compound;

(b) a group which inhibits degradation of the compound by proteolytic enzymes; and

(c) a group which inhibits conjugation of polar groups to the compound in vivo. When the chemical compounds or compositions of the present invention comprise an atom or group which enables the compound to be traced or detected, the said atom or group may be selected from the group consisting of:

(a) a coloured, fluorescent or other spectroscopically detectable atom or group;

(b) an atom which comprises a magnetically active nucleus, selected from the group consisting of: ² H, ¹³ C, ¹⁵ N, ¹⁷ 0, ³³ S, ¹⁹ F, ^35/37 CI, ^79/81 Br and ¹²⁷ I;

(c) a radioactive atom selected from the group consisting of: ³ H, ¹¹ C, ¹⁴ C, ¹³ N, ¹⁵ 0, ³⁵ S, ³⁸ S, ¹⁸ F, ³⁸ CI, ³⁹ CI, ¹²³ 1, ¹²⁵ 1, ¹³¹ I and ⁹⁹ Tc; and

(d) an enzyme, antibody or other detectable protein molecule, or a group derived from a small molecule which binds to an enzyme, antibody or other detectable protein molecule.

When the chemical compounds or compositions of the present invention comprise an atom or group which enhances the ability of the compound to inhibit the aggregation or toxicity of the target amyloid-forming protein or peptide, the said atom or group may be selected from the group consisting of:

(a) a group which binds copper or zinc; and (b) a group which acts as an antioxidant; and

A further aspect of the present invention relates to chemical compounds or compositions wherein each secondary functional component may be independently incorporated into: the peptide backbone; the side chain of X1 , X2, X3, X4 or X5; or a group which is attached to the N- or C-terminal end of the compound.

2.20. Specific examples of chemical compounds

Examples of chemical compounds or compositions according to the present invention, include a modified α-D-isoleucine-containing amino acid sequence which is selected from the group consisting of:

(a) a modified 4-residue amino acid sequence selected from the group consisting of:

H-[(D-lle)-(D-lle)-(D-lle)-(D-mLeu)]-NH ₂ , Me-[(D-lle)-(D-lle)-(D-lle)-(D- mLeu)]-NH ₂ , Me ₂ -[(D-lleHD-lle)-(D-lleHD-mLeu)]-NH ₂ , Ac-[(D-lle)-(D- HeHD-lleHD-mLeu)]-NH _2> Pac-[(D-lle)-(D-lleHD-lle)-(D-mLeu)]-NH ₂ ,

Mac-[(D-lleHD-lleHD-lle)-(D-mLeu)]-NH ₂ , H-[(D-Val)-(D-lle)-(D-Leu)- (D-mLeu)]-NH ₂ , Me-[(D-Val)-(D-lleHD-Leu)-(D-mLeu)]-NH ₂ , Me ₂ -[(D- ValHD-lleHD-LeuHD-mLeu)]-NH ₂ , Ac-[(D-ValHD-lle)-(D-LeuHD- mLeu)]-NH ₂ , Pac-[(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)]-NH ₂ , Mac-[(D- Val)-(D-lleHD-Leu)-(D-mLeu)]-NH ₂ , H-KD-IIe)-(D-IIe)-(D-IIe)-(D-

mLeu)]-NHEt, Me-[(D-lle)-(D-lle)-(D-lle)-(D-mLeu)]-NHEt Me ₂ -I(D- lle)-(D-lle)-(D-lle)-(D-mLeu)]-NHEt, Ac-I(D-IIe)-(D-IIe)-(D-IIe)-(D- mLeu)]-NHEt Pac-[(D-lle)-(D-lle)-(D-lle)-(D-mLeu)]-NHEt, Mac-[(D- HeHD-lle)-(D-lle)-(D-mLeu)]-NHEt, H-KD-VaI)-(D-IIe)-(D-LeU)-(D- mLeu)]-NHEt, Me-[(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)]-NHEt, Me ₂ -I(D-

Val)-(D-lle)-(D-Leu)-(D-mLeu)]-NHEt, Ac-[(D-Val)-(D-lle)-(D-Leu)-(D- mLeu)]-NHEt, Pac-[(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)]-NHEt and Mac- [(D-Val)-(D-lleHD-Leu)-(D-mLeu)]-NHEt; and

(b) a modified 5-residue amino acid sequence selected from the group consisting of:

H-[(lleHD-lle)-(D-lle)-(D-lle)-(D-mLeu)]-NH ₂ , Me-I(IIe)-(D-IIe)-(D-IIe)- (D-lle)-(D-mLeu)]-NH ₂ , Me ₂ -[(lleHD-lle)-(D-lle)-(D-lle)-(D-mLeu)]-NH ₂ , Ac-[(lle)-(D-lleHD-lle)-(D-lle)-(D-mLeu)]-NH ₂ , Pac-[(lle)-(D-lle)-(D-lle)- (D-lle)-(D-mLeu)]-NH ₂ , Mac-[(lle)-(D-lle)-(D-lleHD-lleHD-mLeu)]- NH ₂ , H-[(lle)-(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)]-NH ₂ , Me-[(lle)-(D-Val)-

(D-lle)-(D-Leu)-(D-mLeu)]-NH ₂ , Me ₂ -I(IIe)-(D-VaIHD-IIe)-(D-LeU)-(D- mLeu)]-NH ₂ , Ac-[(lle)-(D-Val)-(D-lleHD-LeuHD-mLeu)]-NH ₂ , Pac- I(lle)-(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)]-NH ₂ , MaC-I(IIe)-(D-VaI)-(D- HeHD-Leu)-(D-mLeu)]-NH ₂ , H-[(lle)-(D-lle)-(D-lleHD-lleHD-mLeu)]- NHEt, Me-[(lle)-(D-lle)-(D-lle)-(D-lleHD-mLeu)]-NHEt, Me ₂ -I(IIe)-(D- lleHD-lle)-(D-lleHD-mLeu)]-NHEt, Ac-I(IIe)-(D-IIe)-(D-IIe)-(D-IIe)-(D- mLeu)]-NHEt, Pac-[(lleHD-lleHD-lle)-(D-lleHD-mLeu)]-NHEt, Mac- I(lleHD-lleHD-lleHD-lleHD-mLeu)]-NHEt, H-I(IIe)-(D-VaI)-(D-IIe)-(D- Leu)-(D-mLeu)]-NHEt, Me-[(lle)-(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)]- NHEt, Me ₂ -[(lle)-(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)]-NHEt, Ac-[(lle)-(D-

. Val)-(D-lleHD-Leu)-(D-mLeu)]-NHEt, PaC-I(IIe)-(D-VaI)-(D-IIe)-(D- Leu)-(D-mLeu)]-NHEt and Mac-[(lle)-(D-Val)-(D-lle)-(D-Leu)-(D- mLeu)]-NHEt; wherein: D-VaI is α-D-valine, D-IIe is α-D-isoleucine, D-Leu is α-D-leucine, D- mLeu is N-methyl-α-D-leucine, H is a free (unmodified) N-terminal amino group, Me is an N-terminal N-methyl amino group, Me ₂ is an N- terminal N,N-dimethyl amino group, Ac is an N-terminal N-acetyl amino group, Pac is an N-terminal N-(1-piperidinyl)acetyl amino group, Mac is an N-terminal N-(4-morpholinyl)acetyl amino group,

NH ₂ is a free C-terminal amide group and NHEt is a C-terminal N- ethyl amide group.

Examples of chemical compounds or compositions according to the present invention include a modified α-D-cyclohexylglycine-containing amino acid sequence which is selected from the group consisting of:

(a) a modified 3-residue amino acid sequence selected from the group consisting of:

H-[(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Me-[(D-ChgHD-Chg)-(D-mLeu)]- NH ₂ , Me ₂ -[(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Ac-[(D-Chg)-(D-ChgHD- mLeu)]-NH ₂ , Pac-[(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Mac-[(D-Chg)-(D-

Chg)-(D-mLeu)]-NH ₂ , H-[(D-lng)-(D-Chg)-(D-mLeu)]-NH ₂ , Me-[(D- lng)-(D-Chg)-(D-mLeu)]-NH ₂ , Me ₂ -[(D-lng)-(D-Chg)-(D-mLeu)]-NH ₂ , Ac-[(D-lngHD-Chg)-(D-mLeu)]-NH ₂ , Pac-[(D-lng)-(D-Chg)-(D-mLeu)]-

NH ₂ , Mac-[(D-lngHD-Chg)-(D-mLeu)]-NH ₂ , H-[(D-Chg)-(D-Chg)-(D- mLeu)]-NHEt, Me-[(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, Me ₂ -[(D-Chg)- (D-Chg)-(D-mLeu)]-NHEt, Ac-[(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, Pac-[(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, Mac-[(D-Chg)-(D-Chg)-(D- mLeu)]-NHEt, H-[(D-lng)-(D-Chg)-(D-mLeu)]-NHEt, Me-[(D-lng)-(D-

Chg)-(D-mLeu)]-NHEt, Me ₂ -[(D-lng)-(D-Chg)-(D-mLeu)]-NHEt, Ac-[(D- lng)-(D-Chg)-(D-mLeu)]-NHEt, Pac-[(D-lng)-(D-Chg)-(D-mLeu)]-NHEt and Mac-[(D-lng)-(D-Chg)-(D-mLeu)]-NHEt;

(b) a modified 4-residue amino acid sequence selected from the group consisting of:

H-[(D-Chg)-(D-ChgHD-Chg)-(D-mLeu)]-NH ₂ , Me-[(D-Chg)-(D-Chg)- (D-Chg)-(D-mLeu)]-NH ₂ , Me ₂ -[(D-Chg)-(D-Chg)-(D-Chg)-(D-mLeu)]- NH ₂ , Ac-[(D-Chg)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Pac-[(D-Chg)-(D- Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Mac-[(D-Chg)-(D-Chg)-(D-Chg)-(D- mLeu)]-NH ₂ , H-[(D-lng)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Me-[(D- lng)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Me ₂ -[(D-lng)-(D-Chg)-(D-Chg)- (D-mLeu)]-NH ₂ , Ac-[(D-lng)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Pac- [(D-lng)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Mac-[(D-lng)-(D-Chg)-(D- Chg)-(D-mLeu)]-NH ₂ , H-[(D-Chg)-(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, Me-[(D-Chg)-(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, Me ₂ -[(D-Chg)-(D-

Chg)-(D-Chg)-(D-mLeu)]-NHEt, Ac-[(D-Chg)-(D-Chg)-(D-Chg)-(D- mLeu)]-NHEt, Pac-[(D-Chg)-(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, Mac- [(D-Chg)-(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, H-[(D-lng)-(D-Chg)-(D- Chg)-(D-mLeu)]-NHEt, Me-[(D-lng)-(D-Chg)-(D-Chg)-(D-mLeu)]- NHEt, Me ₂ -[(D-lng)-(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, Ac-[(D-lng)-(D-

Chg)-(D-Chg)-(D-mLeu)]-NHEt, Pac-[(D-lng)-(D-Chg)-(D-Chg)-(D- mLeu)]-NHEt and Mac-[(D-lng)-(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt; and

(c) a modified 5-residue amino acid sequence selected from the group consisting of:

H-[(D-Chg)-(D-Chg)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Me-[(D-Chg)- (D-Chg)-(D-Chg)-(D-Chg)-(D-ml_eu)]-NH ₂ , Me ₂ -[(D-Chg)-(D-Chg)-(D- Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Ac-[(D-Chg)-(D-Chg)-(D-Chg)-(D-Chg)- (D-mLeu)]-NH ₂ , Pac-[(D-Chg)-(D-Chg)-(D-Chg)-(D-Chg)-(D-mLeu)]- NH ₂ , Mac-[(D-Chg)-(D-Chg)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , H-[(D-

Chg)-(D-lng)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Me-[(D-Chg)-(D-lng)- (D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Me ₂ -[(D-Chg)-(D-lng)-(D-Chg)-(D- Chg)-(D-mLeu)]-NH ₂ , Ac-[(D-Chg)-(D-lng)-(D-Chg)-(D-Chg)-(D- mLeu)]-NH ₂ , Pac-[(D-Chg)-(D-lng)-(D-Chg)-(D-ChgHD-mLeu)]-NH ₂ , Mac-[(D-Chg)-(D-lng)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , H-f(D-Chg)-

(D-Chg)-(D-ChgHD-Chg)-(D-mLeu)]-NHEt, Me-[(D-Chg)-(D-Chg)-(D- Chg)-(D-Chg)-(D-mLeu)]-NHEt, Me ₂ -[(D-Chg)-(D-Chg)-(D-Chg)-(D- Chg)-(D-mLeu)]-NHEt, Ac-[(D-Chg)-(D-Chg)-(D-Chg)-(D-Chg)-(D- mLeu)]-NHEt, Pac-[(D-Chg)-(D-Chg)-(D-Chg)-(D-Chg)-(D-mLeu)]- NHEt, Mac-[(D-Chg)-(D-Chg)-(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, H-

[(D-ChgHD-lng)-(D-Chg)-(D-ChgHD-mLeu)]-NHEt, Me-[(D-Chg)-(D- lng)-(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, Me ₂ -[(D-Chg)-(D-lng)-(D- Chg)-(D-Chg)-(D-mLeu)]-NHEt, Ac-[(D-Chg)-(D-lng)-(D-Chg)-(D- Chg)-(D-mLeu)]-NHEt, Pac-[(D-Chg)-(D-lng)-(D-Chg)-(D-Chg)-(D- mLeu)]-NHEt and Mac-[(D-Chg)-(D-lng)-(D-Chg)-(D-Chg)-(D-mLeu)]~

NHEt; and Me-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Me ₂ -[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Ac-[(D-Chg)- (D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ , Pac-[(D-Chg)-(D-Tyr)-(D- Chg)-(D-Chg)-(D-mLeu)]-NH ₂ and Mac-[(D-Chg)-(D-Tyr)-(D-Chg)-(D~ Chg)-(D-ml_eu)]-NH ₂ , Yac-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D- mLeu)]-NH ₂ ;

Me-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, Me ₂ -[(D- Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, Ac-[(D-Chg)-(D-Tyr)- (D-Chg)-(D-Chg)-(D-mLeu)]-NHEt, Pac-[(D-Chg)-(D-Tyr)-(D-Chg)-(D- Chg)-(D-mLeu)]-NHEt and Mac-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-

(D-mLeu)]-NHEt, Yac-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]- NHEt; wherein:

D-Chg is α-D-cyclohexylglycine, D-lng is α-D-indanylglycine, D-mLeu is N- methyl-α-D-leucine, H is a free (unmodified) N-terminal amino group, Me is an N-terminal N-methyl amino group, Me ₂ is an N-terminal N,N-dimethyl amino group, Ac is an N-terminal N-acetyl amino group, Pac is an N- terminal N-(1-piperidinyl)acetyl amino group, Mac is an N-terminal N-(4- morpholinyl)acetyl amino group, Yac is an N-terminal N-(1 -pyrrolidinyl) acetyl amino group, NH ₂ is a free C-terminal amide group and NHEt is a C- terminal N-ethyl amide group.

Although the above examples represent chemical compounds and compositions which fall within the scope of the present invention, it should be recognised that the general concept of the present invention can be applied across a wide range of chemical compounds and compositions.

2.21. Physical and chemical properties

The present invention includes any chemical compound or composition, wherein the compound or composition has any combination of 1 , 2, 3, 4, 5, 6 or more physical or chemical properties selected from the group consisting of:

(a) a molecular weight of less than 2,000, 1 ,500, 1 ,200, 1 ,000, 900, 800, 700, 600 or 500 Da;

(b) no more than 12, 11 , 10, 9, 8, 7, 6, 5, 4, 3 or 2 hydrogen bond donors in total;

(c) no more than 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5 or 4 hydrogen bond acceptors in total;

(d) no more than 25, 22, 20, 18, 16, 15, 14, 13, 12, 11 or 10 rotatable bonds in total; (e) a total polar surface area of less than 400, 350, 300, 250, 200, 150,

120, 100, 80 or 60 A ² ;

(f) a logD, logP or a calculated logP value of no less than 1.0, 1.5, 2.0 or 2.5 and no more than 3.0, 3.5, 4.0, 4.5 or 5.0;

(g) solubility in water to a concentration of at least 1 , 10, 100, 1 ,000 or 10,000 μM;

(h) solubility in octanol to a concentration of at least 1 , 10, 100, 1 ,000 or 10,000 μM; and

(i) ability to pass through the gut wall, nasal mucosa, pulmonary epithelium, skin, blood-brain barrier, cell membranes, or any other biological membrane or barrier.

2.22. Functions and activities

The present invention may also include any chemical compound or composition, wherein the amyloid-binding peptide sequence or the compound or composition as a whole performs any 1 , 2, 3, 4, 5, 6, 7, 8, 9,

10 or more functions or activities independently selected from the group consisting of:

(a) bind to a monomeric or oligomeric form of the target amyloid-forming protein or peptide; (b) bind to soluble oligomers, protofibrils or ion channels formed by the target amyloid-forming protein or peptide;

(c) bind to a misfolded or aggregated form of the target amyloid-forming protein or peptide;

(d) bind to insoluble amyloid fibres, plaques or inclusions formed by the target amyloid-forming protein or peptide;

(e) bind to a target amino acid sequence within the target amyloid- forming protein or peptide;

(f) bind to a β-strand formed by a section of the target amyloid-forming protein or peptide; (g) inhibit, reverse or otherwise modulate the intermolecular association of β-strands formed by the target amyloid-forming protein or peptide;

(h) inhibit, reverse or otherwise modulate the formation of intermolecular β-sheets by the target amyloid-forming protein or peptide;

(i) inhibit, reverse or otherwise modulate oligomerisation or aggregation of the target amyloid-forming protein or peptide;

G) inhibit, reverse or otherwise modulate the formation of soluble oligomers, protofibrils or ion channels by the target amyloid-forming protein or peptide;

(k) inhibit, reverse or otherwise modulate the formation of insoluble amyloid fibres, plaques or inclusions by the target amyloid-forming protein or peptide;

(I) inhibit, reduce or modulate the toxicity of the target amyloid-forming protein or peptide;

(m) inhibit, reduce or otherwise modulate the toxicity of soluble oligomers, protofibrils or ion channels formed by the target amyloid-forming protein or peptide;

(n) inhibit, reduce or otherwise modulate the toxicity of insoluble amyloid fibres, plaques or inclusions formed by the target amyloid-forming protein or peptide;

(o) promote or facilitate the conversion of soluble oligomers, protofibrils or ion channels or any other toxic form of the target amyloid-forming protein or peptide into a less toxic form;

(p) promote or facilitate in vivo degradation or clearance of the target amyloid-forming protein or peptide;

(q) promote or facilitate the in vivo degradation or clearance of soluble oligomers, protofibrils or ion channels formed by the target amyloid- forming protein or peptide;

(r) promote or facilitate the in vivo degradation or clearance of insoluble amyloid fibres, plaques or inclusions formed by the target amyloid- forming protein or peptide; (s) inhibit, reverse or otherwise modulate the pathogenic process of amyloidosis associated with an amyloid-related disease;

(t) inhibit, reverse or otherwise modulate the onset or progression of an amyloid-related disease;

(u) inhibit, reverse or otherwise modulate the oxidative stress or generation of toxic free radicals associated with an amyloid-related disease; and

(v) inhibit, reverse or otherwise modulate the neuroinflammation associated with a neurological amyloid-related disease.

2.23. Methods of preparation

In another aspect, the present invention provides a method of preparing the compounds or compositions of the present invention by linking the appropriate N-9-fluorenylmethoxycarbonyl (Fmoc) or N-ferf-butoxycarbonyl (Boc)-protected amino acids or amino acid analogues or derivatives, together with any N- or C-terminal modifying groups using standard methods of solid-phase or solution-phase peptide synthesis with a suitable coupling agent.

In the aforementioned method, the compounds or compositions are prepared essentially as described herein using the appropriate amino acid analogues or derivatives and other building blocks. Examples of methods which may be used are discussed in Example 1.

2.24. Compound libraries

The chemical compounds or compositions of the present invention may be part of a combinatorial chemical library or a collection of compounds.

The combinatorial chemical library or a collection of compounds may comprise at least 1 , 10, 100 or more chemical compounds or compositions as disclosed herein.

Preferably, at least 1%, 2%, 5%, 10%, 20%, 50%, 80% or 100% of the compounds in the combinatorial chemical library or collection of compounds are chemical compounds or compositions, as disclosed herein.

The compounds or compositions which are part of the combinatorial chemical library, or the collection of compounds, may be prepared, stored, tested or used either individually or as a mixture.

2.25. Methods of selection and optimisation

Another aspect of the present invention relates to a method for selecting or identifying a compound that binds to the target amyloid-forming protein or peptide, or to a target amino acid sequence, wherein:

(a) a combinatorial chemical library or a collection of compounds is screened using a suitable binding assay in which the target amyloid- forming protein or peptide, or target amino acid sequence, is attached to a solid matrix, resin or other solid support;

(b) at least one of the compounds in the combinatorial chemical library or compound collection is a chemical compound as disclosed herein;

(c) the binding assay is optionally an affinity chromatography assay, wherein: i. the compounds are added to a column containing a solid matrix or resin to which the target amyloid-forming protein or peptide, or target amino acid sequence is attached; ii. the compounds are eluted from the column using a suitable solvent, and their elution from the column is monitored using a suitable detection method; and iii. the relative binding affinity of each compound is determined by the concentration of solvent required to elute each compound from the column;

(d) the target amino acid sequence is any hydrophobic amino acid sequence derived from within the target amyloid-forming protein or peptide;

(e) the same compounds are optionally screened again using the same binding assay, but with a different protein or peptide sequence attached to the same solid matrix, resin or support; and (f) the relative binding affinities of the compounds are compared to select a specific compound, or to identify any desirable structural features which are combined and incorporated into an improved chemical compound which binds more tightly or selectively to the target amyloid-forming protein or peptide, or to the target amino acid sequence.

An example of the aforementioned method is shown in Example 2.

The present invention further relates to any compound which is selected or identified by the above method.

2.25. Target proteins and peptides

In another aspect, the present invention relates to chemical compounds or compositions wherein the target amyloid-forming protein or peptide is any protein or peptide which misfolds or aggregates into toxic soluble oligomers, protofibrils, ion channels, insoluble amyloid fibres, plaques or inclusions (or any form of deposits).

The target amyloid-forming protein or peptide can be selected from, but is not limited to, the group consisting of:

(a) β-amyloid peptide, Aβ(1-40) or Aβ(1-42), or any mutant, fragment or derivative thereof, which is associated with Alzheimer's disease, senile dementia, mild cognitive impairment (MCI), Down's syndrome, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with I amyloidosis (HCHWA, Dutch type), inclusion body myositis or age- related macular degeneration (ARMD); (b) tau protein, or any mutant, peptide fragment or derivative thereof, which is associated with any form of Alzheimer's disease (AD or FAD) or fronto-temporal dementia;

(c) α-synuclein protein, or any mutant, fragment or derivative thereof, which is associated with any form of Parkinson's disease (PD) or dementia with Lewy bodies;

(d) a protein or peptide comprising a polyglutamine peptide sequence, which is associated with Huntington's disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinocerebellar ataxia (SCA, types 1 , 2, 3, 6 and 7), spinal and bulbar muscular atrophy (SBMA, Kennedy's disease), or any other polyglutamine disease;

(e) any prion protein, or any mutant, peptide fragment or derivative thereof, which is associated with Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE) in cows, scrapie (sheep), kuru, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia, or any other transmissible encephalopathy;

(f) superoxide dismutase protein, or any mutant, peptide fragment or derivative thereof, which is associated with amyotrophic lateral sclerosis (ALS) or any form of motor neuron disease;

(g) ABri or ADan peptide sequence of the BRI protein, associated with familial British dementia (FBD) and familial Danish dementia (FDD), respectively;

(h) cystatin C protein, or any mutant, peptide fragment or derivative thereof, which is associated with hereditary cerebral hemorrhage with amyloidosis (HCHWA, Icelandic type); (i) the islet amyloid polypeptide (IAPP), or any mutant, peptide fragment or derivative thereof, which is associated with type Il diabetes (also known as adult onset diabetes, or non-insulin dependent diabetes mellitus, NIDDM);

(j) β ₂ -microglobulin protein, or any mutant, fragment or derivative thereof, which is associated with dialysis-related amyloidosis (DRA) or prostatic amyloid;

(k) immunoglobulin light chain, or any mutant, peptide fragment or derivative thereof, which is associated with primary systemic amyloidosis, systemic AL amyloidosis, or nodular AL amyloidosis;

(I) AH amyloid protein from immunoglobulin heavy chain, or any mutant, peptide fragment or derivative thereof, which is associated with myeloma associated amyloidosis;

(m) Serum amyloid A protein, or any mutant, peptide fragment or derivative thereof, which is associated with reactive systemic AA amyloidosis, secondary systemic amyloidosis, chronic inflammatory disease, or familial Mediterranean fever;

(n) transthyretin protein, or any mutant, fragment or derivative thereof, which is associated with senile systemic amyloidosis, familial amyloid polyneuropathy, or familial cardiac amyloid;

(o) lysozyme protein, or any mutant, peptide fragment or derivative thereof, which is associated with familial visceral amyloidosis, hereditary non-neuropathic systemic amyloidosis, or any other lysozyme-related amyloidosis;

(p) gelsolin protein, or any mutant, peptide fragment or derivative thereof, which is associated with Finnish hereditary systemic amyloidosis; (q) fibrinogen α-chain, or any mutant, fragment or derivative thereof, which is associated with fibrinogen α-chain amyloidosis;

(r) insulin protein, or any mutant, peptide fragment or derivative thereof, which is associated with insulin-related amyloidosis;

(s) calcitonin protein, or any mutant, peptide fragment or derivative thereof, which is associated with medullary carcinoma of the thyroid;

(t) atrial natriuretic factor, or any mutant, fragment or derivative thereof, which is associated with isolated atrial amyloidosis;

(u) γ-crystallin S or γ-crystallin D, or any mutant, peptide fragment or derivative thereof, which is associated with any form of cataract. In a further aspect, the amyloid-binding peptide sequence of the chemical compounds or compositions of the present invention binds to a target amino acid sequence within the target amyloid-forming protein or peptide, said target amino acid sequence being selected from, but not limited to, the group consisting of: (a) any section of the target amyloid-forming protein or peptide which plays an essential role in the aggregation of the target amyloid- forming protein or peptide;

(b) any section of the target amyloid-forming protein or peptide which forms an intermolecular β-sheet interaction in an aggregated form of the target amyloid-forming protein or peptide;

(c) any section of the target amyloid-forming protein or peptide which forms insoluble amyloid fibres, plaques or inclusions as an isolated peptide; and

(d) any hydrophobic amino acid sequence within the target amyloid- forming protein or peptide.

Target amino acid sequences within the target amyloid-forming protein or peptide to which the amyloid-binding peptide sequences of the present invention bind can be selected from, but are not limited to, the group consisting of:

(a) KLVFFAE or I IGLMVGGVV(IA) within human β-amyloid peptide Aβ(1- 40) or Aβ(1-42);

(b) SVQIVYK or KVQIINK within the human tau protein; (c) GAVVTGVTAVAQKTV within the human α-synuclein protein;

(d) a sequence of 4, 5, 6, 7, 8, 9, 10 or more consecutive glutamine residues (polyglutamine);

(e) AGAAAAGAWGGLG within any prion protein;

(f) ATKAVCVL, VQGIINF, IIGRTLW or LACGVIGIA within human superoxide dismutase;

(g) FAIRHFE or FAVETLI within the ABri/ADan peptide sequence of the human BRI protein;

(h) QIVAGVNYFLD or AFCSFQIYAV within the human cystatin C protein; (i) LANFLV or NFGAILS within the human islet amyloid polypeptide;

(j) SFYLLYYT within the human β ₂ -microglobulin protein;

(k) any hydrophobic amino acid sequence within human immunoglobulin light chain;

(I) any hydrophobic amino acid sequence within human immunoglobulin heavy chain;

(m) SFFSFLG within the human Serum amyloid A protein;

(n) LMVKVL, INVAVHVF, EWFTAN, YTIAALLS or YSTTAWT in human transthyretin;

(o) LANWMCLA or AWVAW within the human lysozyme protein; (p) DAYVILK, SYIILYNY, AYLWVG, QVFVWVG or FVGWFLGW within human gelsolin;

(q) WWVSF within the α-chain of human fibrinogen;

(r) LVEALYLV within human insulin;

(s) LLLAALV within the human calcitonin protein; (t) LRALLTA within human atrial natriuretic factor;

(u) GTWAVYE or GVWIFYE within the human γ-crystallin S protein; and

(v) GCWMLYE or GSWVLYE within the human γ-crystallin D protein.

2.26. Pharmaceutical compositions and formulations

Another aspect of the present invention provides pharmaceutical compositions or formulations comprising, or consisting of, a chemical compound or composition of the present invention. The pharmaceutical compositions or formulations of the present invention may comprise 1 , 2, 3, 4 or more additional compounds. The additional compounds can be independently selected from, but are not limited to, the group consisting of:

(a) a compound which enhances the overall bioavailability of the chemical compound in vivo;

(b) a compound which enhances the absorption of the chemical compound through the gut wall, nasal mucosa, pulmonary epithelium, blood-brain barrier, cell membranes, skin, or any other biological membrane or barrier; (c) a compound which enhances delivery of the compound to a target organ;

(d) a compound which enhances the solubility of the compound;

(e) a compound which enhances the chemical or biological stability of the compound; (f) a compound which reduces the metabolism or clearance of the compound in vivo; and

(g) a compound which enhances the prevention or treatment of any amyloid-related disease.

The pharmaceutical compositions or formulations may be administered to a subject by any means of delivery selected from, but not limited to, the group consisting of:

(a) oral delivery;

(b) intravenous injection;

(c) pulmonary delivery; (d) nasal delivery;

(e) buccal delivery;

(f) rectal delivery;

(g) transdermal delivery; (h) subcutaneous delivery; (i) ocular delivery;

G) intrathecal delivery; and (k) intracranial delivery.

Depending on the route of administration, the chemical compound or composition may be required to be coated in a material to protect it from the action of enzymes, acids and other natural conditions which may inactivate it.

In order to administer the chemical compound or composition by other than parenteral administration, it may be coated by, or administered with, a material to prevent its inactivation. For example, it may be administered in an adjuvant, co-administered with enzyme inhibitors or in liposomes.

Adjuvant is used in its broadest sense and includes any immune stimulating compound such as interferon. Adjuvants contemplated herein include resorcinols, non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether. Enzyme inhibitors include those of pancreatic trypsin and other digestive proteases.

Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes. The active chemical compound or composition may also be administered parenterally or intraperitoneally. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical compositions or formulations suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene gloycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of superfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thirmerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active che'mical compound or composition in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield

a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.

When the chemical compound or composition is suitably protected as described above, it may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier.

Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and formulations.

As used herein "pharmaceutically acceptable carrier and/or diluent" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. • The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such

as active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired.

The principal active ingredients are compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.

2.27. Therapeutic and Diagnostic uses and methods

The present invention further provides for the use of a chemical compound or composition of the present invention in the manufacture of a medicament for the treatment of any amyloid-related disease. A further aspect of the present invention provides a method for the treatment of any amyloid-related disease in a subject, wherein a chemical compound or composition of the present invention is administered to the subject.

A still further aspect of the present invention provides the use of a chemical compound or composition of the present invention in the manufacture of an agent for the diagnosis of any amyloid-related disease.

Another aspect of the present invention provides a method for the diagnosis of any amyloid-related disease in a subject, wherein a chemical compound or composition of the present invention is administered to the subject. Amyloid-related diseases referred to hererin include, but are not limited to:

(a) any form of Alzheimer's disease (AD or FAD);

(b) any form of mild cognitive impairment (MCI) or senile dementia;

(c) Down's syndrome;

(d) cerebral amyloid angiopathy, inclusion body myositis, hereditary cerebral hemorrhage with amyloidosis (HCHWA, Dutch type), or age- related macular degeneration (ARMD);

(e) fronto-temporal dementia;

(f) any form of Parkinson's disease (PD) or dementia with Lewy bodies;

(g) Huntington's disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinocerebellar ataxia (SCA, types 1, 2, 3, 6 and 7), spinal and bulbar muscular atrophy (SBMA, Kennedy's disease), or any other polyglutamine disease;

(h) Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy

(BSE) in cows, scrapie in sheep, kuru, Gerstmann-Straussler- Scheinker disease (GSS), fatal familial insomnia, or any other transmissible encephalopathy that is associated with the aggregation of prion proteins;

(i) amyotrophic lateral sclerosis (ALS) or any other form of motor neuron disease;

0) familial British dementia (FBD) or familial Danish dementia (FDD);

(k) hereditary cerebral hemorrhage with amyloidosis (HCHWA, Icelandic type);

(I) type Il diabetes (adult onset diabetes, or non-insulin dependent diabetes mellitus, NlDDM);

(m) dialysis-related amyloidosis (DRA) or prostatic amyloid;

(n) primary systemic amyloidosis, systemic AL amyloidosis, or nodular AL amyloidosis;

(o) myeloma associated amyloidosis; (p) systemic (reactive) AA amyloidosis, secondary systemic amyloidosis, chronic inflammatory disease, or familial Mediterranean fever;

(q) senile systemic amyloidosis, familial amyloid polyneuropathy, or familial cardiac amyloid;

(r) familial visceral amyloidosis, hereditary non-neuropathic systemic amyloidosis, or any other lysozyme-related amyloidosis;

(s) Finnish hereditary systemic amyloidosis;

(t) fibrinogen α-chain amyloidosis;

(u) insulin-related amyloidosis;

(v) medullary carcinoma of the thyroid; (w) isolated atrial amyloidosis;

(x) any form of cataract; and

(y) any other amyloid-related disease that is associated with the misfolding or aggregation of a specific target amyloid-forming protein or peptide into toxic soluble oligomers, protofibrils, ion channels, insoluble amyloid fibres, plaques or inclusions.

The diagnosis of an amyloid-related disease can be made by in vivo imaging of the chemical compound or composition in the subject. Alternatively, diagnosis may be carried out ex vivo, on a sample removed from a subject. The in vivo imaging of the chemical compound or composition in the subject can be carried out using a technique selected from the group consisting of: computed tomography (CT), positron emission tomography (PET) and nuclear magnetic resonance imaging (MRI).

3. BREIF DESCRIPTION OF THE FIGURES

Figure 1 (a to d) shows the binding affinities of various test peptides for alternative target amino acid sequences, plotted against those for the KLVFFAE target amino acid sequence of Aβ(1-42), based on the binding affinity data provided in Table 2:

(I) NFGAILS target amino acid sequence of IAPP (associated with type K diabetes)

(m) AWTGVTA target amino acid sequence of α-synuclein (Parkinson's disease, PD) (n) SFYLLYYT target amino acid sequence of β ₂ M (dialysis-related amyloidosis, DRA)

(o) GVWlFYE target amino acid sequence of γ-crystallin S protein (cataracts)

From these graphs, it is clear that some of the peptides are more selective for one particular target amino acid sequence over another, while others bind with high affinity to more than one amyloid-forming target peptide sequence.

Figure 2 (a to d) shows various other correlations based on the binding affinity and activity data provided in Table 2:

(a) Binding affinities of various test peptides for the KLVFFAE target amino acid sequence of Aβ(1-42), plotted against molecular weight, showing that many of the small peptides (MW <750 Da) bind to Aβ(1- 42) with high affinity (30-80% acetonitrile required for elution). (b) % amyloid (ThT assay) formed by 10 μM Aβ(1-42) in the presence of various test peptides at 5 μM, plotted against binding affinity for the KLVFFAE target amino acid sequence of Aβ(1-42), showing a general correlation between the inhibitory activity and binding affinity of peptides, with some scatter due to experimental error of ThT assay (up to about 20%).

(c) % PC12 cell viability (MTT assay) in presence of 10 μM Aβ(1 -42) with various test peptides at 5 μM, plotted against binding affinity for the KLVFFAE target amino acid sequence of Aβ(1-42), showing a general correlation between the inhibitory activity and binding affinity of peptides, with some scatter due to experimental error of MTT assay

(up to about 20%).

(d) % amyloid (ThT assay) formed by 10 μM Aβ(1-42) in the presence of various test peptides at 5 μM, plotted against % PC12 cell viability (MTT assay) using the same concentrations, showing a general correlation between the inhibitory activity of peptides measured by each assay.

Figure 3 (a and b) shows dose response curves of % amyloid formation (ThT assay) by 10 μM Aβ(1-42) in the presence of various test peptides,

plotted against peptide concentration. In each case, amyloid formation is significantly inhibited by 10 μM test peptide (1 :1 molar ratio).

Figure 4 (a and b) shows dose response curves of % PC12 cell viability (MTT assay) in presence of 10 μM Aβ(1-42) with various test peptides, plotted against peptide concentration. In each case, amyloid toxicity is significantly inhibited by 10 μM test peptide (1 :1 molar ratio).

Figure 5 (a and b) shows the effect of 1 nM Aβ(1-40) on long-term potentiation (LTP) along the Schaffer collaterals in rat hippocampal brain slices, alone and in the presence of SEN-304 at three different concentrations: 1 μM (1 ,000:1), 10 nM (10:1) and 1 nM (1 :1) (as described in Example 4). Whereas 1 nM Aβ(1-40) alone potently inhibits LTP (mean amplitude after 60 min is reduced from 158% to 120% control), this toxic effect of 1 nM Aβ(1 -40) on LTP is effectively blocked by SEN-304 at all 3 concentrations tested (mean amplitude after 60 min remains high at 164%, 150% and 150% control, respectively).

Figure 6 (a to f) shows various molecular models to illustrate how just one particular example of an amyloid-binding peptide, Pac-[(D-Chg)-(D-Tyr)-(D-

Chg)-(D-Chg)-(D-mLeu)]-NH ₂ (SEN-606), might bind to the KLVFFAE target amino acid sequence of Aβ(1-42):

(a) Space-filling model of two-stranded antiparallel β-sheet formed by KLVFFAE target amino acid sequence of Aβ(1-42) - "top view", showing possible packing of hydrophobic Leu, Phe and Ala side chains on one side of the β-sheet.

(b) Model of Fig 6(a) with SEN-606 bound to form three-stranded antiparallel β-sheet, showing possible packing of hydrophobic side chains on same side of the associated β-sheet complex. (c) "Bottom view" of model shown in Fig 6(a), showing possible packing of Lys, VaI, Phe and GIu side chains on other side of the two-stranded antiparallel β-sheet formed by KLVFFAE target amino acid sequence.

(d) Model of Fig 6(c) with SEN-606 bound to form three-stranded antiparallel β-sheet, showing possible packing of hydrophobic side chains on the other side of the β-sheet complex.

(e) Space-filling model of SEN-606 in extended β-strand conformation - "side view", showing potential amyloid-binding surface, possibly involved in binding to KLVFFAE target amino acid sequence of Aβ(1- 42). (f) Schematic representation of Fig 6(e) showing key features of the proposed amyloid-binding surface of SEN-606: an extended peptide backbone which comprises a regular sequence of hydrogen bond donors and acceptors (with the appropriate spacing to match that of a target β-strand); and a relatively flat but flexible hydrophobic surface

above and below the peptide backbone, comprising favourably packed hydrophobic side chains.

These molecular models are shown to illustrate just one potential mode of interaction, and are not intented to limit the scope of the invention in any way.

The invention is further described, for the purposes of illustration only, in the following examples. It will, however, be appreciated that the general concept of the present invention may be applied across a wide range of chemical compounds and compositions.

4. EXAMPLES

Example 1 - Synthesis and purification of amyloid-binding peptides

All peptides listed in Table 1 were prepared by standard methods of λ/-9- fluorenylmethoxycarbonyl (Fmoc)-based solid phase peptide synthesis as described below, however they could be synthesised just as well by N-tert- butoxycarbonyl (Boc)-based solid phase synthesis, or by Fmoc- or Boc- based solution phase peptide synthesis, using similar known methods. All peptides having a C-terminal amide group were synthesised on Rink amide resin, except those comprising an acetylated λ/-methyl amino acid residue at the N-terminus (not included in Table 1 ), which were synthesised on Seiber amide resin due to the instability of those peptides in the strong acid conditions required for Rink amide cleavage. The Rink amide resin or Seiber amide resin was Fmoc deprotected using the Fmoc deprotection method described below, then loaded with the first λ/-α-Fmoc-amino acid using coupling Method A (as described below). The N-α-Fmoc group was removed prior to adding the next amino acid residue. If the previous amino acid was λ/-methylated, then the next λ/-α-Fmoc amino acid was coupled using Method B (described below), otherwise the next /V-α-Fmoc amino acid was coupled using Method A, as indicated in Table 1.

Further cycles of coupling and deprotection were performed using the appropriate Method, A or B (depending upon the previous amino acid which was coupled to the resin), followed by N-α-Fmoc deprotection until the required peptide sequence was achieved.

SEN-618 was prepared on 4-(4-formyl-3-methoxyphenoxy)butyryl AM resin. The primary amine was attached to the resin by reductive amination. The resin was swollen in dichloroethane (DCE) for 1 hour. The amine (10eq) was dissolved in dichloromethane (DCM)/trimethy!orthoformate (2:1) and added to the resin. NaBH(OAc) ₃ (10eq) was added and the resin shaken overnight. The resin was washed with dimethylformamide (DMF), 10% N,N-diisopropylethylamine (DIPEA) in DMF, then DMF. The first amino acid was coupled to the resin using coupling Method A, except 2-(6-chloro- 1 H-benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate was used as the coupling agent.

If the N-terminus of the peptide is acetylated, then following Fmoc deprotection of the final amino acid residue, the peptidyl-resin was treated with acetic anhydride (100μl) and pyridine (100μl) in DMF (2ml) and shaken at room temperature (10 min). The resin was washed with DMF (2 x 2 ml, 2 min each) then DCM (2 x 2 ml, 2 min each). The peptidyl-resin was vacuum dried to remove all traces of solvent prior to cleavage and isolation of the peptide as described in the methods 'Peptide Cleavage - Seiber amide resin' and 'Peptide Cleavage - Rink amide resin' (see below).

SEN-602 and SEN-603 were synthesised as described above up to the point of adding the modified N-terminal residue. The peptidyl-resin was treated with 1.5eq of either Boc-Me-(D-Chg)-OH (for SEN-602) or Me ₂ -(D- Chg)-OH (SEN-603) and PyBrOP (1.5eq) in DMF (2ml) with DIPEA (4.5eq)

and shaken at room temperature (60 min). The resin was washed with DMF (2 x 2 ml, 2 min each) then DCM (2 x 2 ml, 2 min each). A portion of the resin was tested by qualitative ninhydrin assay, and if a blue colour was produced, indicating incomplete coupling, the coupling step was repeated. SEN-604 to SEN-611 were synthesised as described above up to the point of adding the N-terminal modification to the N-terminal residue. The peptidyl-resin was treated with the appropriate reagent (e.g., N-morpholinyl acetic acid for SEN-604, 605, or N-piperidinyl acetic acid for SEN-606, 607) (2-3 eq) and N,N'-diisopropylcarbodiimide (2-3 eq) in DMF (2ml) and shaken at room temperature (60 min). The resin was washed with DMF (2 x 2 ml, 2 min each) and then DCM (2 x 2 ml, 2 min each). A portion of the resin was tested with a qualitative ninhydrin assay, and if a blue colour was produced, indicating incomplete coupling, the coupling step was repeated.

Coupling Method A

For each coupling step, the appropriate N-α-Fmoc-protected amino acid (3 equivalents to the resin-bound amine), 2-(1 H-benzotriazol-1-yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate (HBTU, 3eq) and 1-hydroxy- benzotriazole (HOBt, 3eq) were added to the resin in DMF (2ml) with DIPEA (9eq). The resin was shaken at room temperature (45-60 min) and washed with DMF (2 x 2 ml, 2 min each). A portion of the resin was tested with a qualitative ninhydrin assay, and if a blue colour was produced, indicating incomplete coupling, the coupling step was repeated before prodeeding to the next stage of the synthesis.

Coupling Method B

For each coupling step, the appropriate N-α-Fmoc protected amino acid (3 equivalents to the resin-bound amine) and bromo-tris-pyrrolidino- phosphonium hexafluorophosphate (PyBrOP, 3eq) were added to the resin in DMF (2ml) with DIPEA (9eq). The resin was shaken at room temperature for 2-4 hr and then washed with DMF (2 x 2 ml, 2 min each). A repeat cycle of this coupling step was performed before proceeding to the next stage of the synthesis.

Fmoc Deprotection

The N-terminal Fmoc protecting group was removed by treating the Fmoc- protected peptidyl-resin with 20% (v/v) piperidine in DMF (2 x 2ml, 5 min then 20 min). The resin was washed with DMF (3 x 2 ml, 2 min each) and tested for a free primary amine by a qualitative ninhydrin assay.

Peptide Cleavage - Seiber amide resin

Peptides synthesised on Seiber amide resin were cleaved in 10% TFA/DCM (3 x 1 ml, 20 min each) and washed with DCM (2 x 2ml, 2 min each). The solutions from the cleavage and washing cycles were pooled and evaporated. The crude product was dissolved in 50% (v/v) acetonitrile/water then freeze-dried prior to purification (see below).

Peptide Cleavage - Rink amide resin

Peptides synthesised on Rink amide resin were cleaved in 50% TFA/DCM (3 x 1ml, 20 min each) and washed with DCM (2 x 2ml, 2 min each). The solutions from the cleavage and washing cycles were pooled and evaporated. The resin was further treated with 80% TFA/DCM (3 x 1ml, 20 min each) and washed with DCM (2 x 2ml, 2 min each). The solutions from the cleavage and washing cycles were pooled and evaporated. The crude product from the 50% and 80% TFA cleavage and washing cycles was dissolved in 50% (v/v) acetonitrile/water, pooled and then freeze-dried prior to purification (see below).

Synthesis of Boc-protected N-methyl-α-D-cyclohexylglycine (for SEN-602)

Boc-(D-Chg)-OH was dissolved in THF and methyl iodide (3eq) was added. The reaction mixture was cooled on an ice bath and sodium hydride (3eq) was added. The ice bath was removed and the reaction was stirred at room temperature overnight. The THF solvent was removed and the residue dissolved in ethyl acetate and acidified with HCI. This was washed with dilute HCI and water, and the solution was dried (NaSO ₄ ), filtered and evaporated.

Synthesis of N.N-dimethyl-α-D-cyclohexylglycine (for SEN-603)

H ₂ N-(D-Chg)-OH was dissolved in THF and methyl iodide (5eq) was added. The reaction mixture was cooled on an ice bath and sodium hydride (5eq) was added. The ice bath was removed and the reaction stirred at room temperature overnight. The solvent was removed and the residue dissolved in ethyl acetate and acidified with dilute HCI. This was washed with dilute HCI and water, and the solution was dried (NaSO ₄ ), filtered and evaporated.

Peptide Purification

The crude peptide was dissolved in DMSO to a concentration of 1 to 10 mg/mL (depending upon its solubility). The peptide solution was purified by reverse-phase HPLC using a C-18 semi-prep column (10mm x 250mm, 10 μm particle size, 100 A pore size), employing the following solvent gradient of 0.1 % TFA in water (buffer A) / 0.1 % TFA in acetonitrile (buffer B), over 60 minutes, monitoring absorbance at 220 nm. The peak fractions were collected and freeze-dried.

%A %B Time (min) Flow (mL/min) 80 20 0 5

20 80 60 , 5

Following the reverse-phase HPLC purification procedure described above, peptides are obtained as their trifluoroacetate (TFA) salts. If the HCI salt is required, this was achieved by dissolving the peptide-TFA salt in 50% acetonitrile/water (5 mL) and adding 0.1 M HCI to the solution (10 to 50

equivalents). The solution was freeze-dried. This HCI treatment and freeze-drying procedure was then repeated to ensure full conversion to the HCI salt.

Peptide Analysis

After freeze-drying, a portion of the solid peptide (0.5 mg) was dissolved in 50% acetonitrile/water (0.5 ml_). A 50 μL aliquot of this solution was subjected to analytical reverse phase HPLC (C-18, 4.6mm x 150mm, 5 μm particle size, 90 A pore size), by applying the following solvent gradient of

10 0.1% TFA in water (buffer A) / 0.1% TFA in acetonitrile (buffer B), over 20 minutes, monitoring absorbance at 216 nm.

%A %B Time (min) Flow (mL/min)

100 0 0 1

20 80 20 1

15 The peptides were subjected to electrospray mass spectroscopy (ESMS) analysis to confirm their identity.

Table 1 (a)

Amino acid coupling method Molecular weight (Da)

Code Peptide sequence X1 X2 X3 X4 X5 Mcalc [MtH] ⁺

C1 Ac-[(L-Ser)-(L-Lys)-(L-Ser)-(G!y)-(L-Tyr)]-NH ₂ A A A A A 567.60 568.37

C2 Ac-t(L-Tyr}-(Gly)-(L-Ser)-(L-Lys)-(L-Ser)]-NH ₂ A A A A A 567.60 568.34

J26 Ac-[(L-Leu)-(L-ProHL-Phe)-(L-Phe)-(L-Asp)]-NH ₂ A A A A A 678.78 679.52

SEN-301* H-[(D-Chg)-(D-Cha)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 715.02 715.77

SEN-302* H-[(D-Cha)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ - A A B A 575.83 576.68

SEN-303* H-[(D-Cha)-(D-Cha)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 729,05 730.71

SEN-304* H-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH2 A A A B A 724.98 725.67

SEN-305* H-t(D-Chg)-(D-Cha)-(D-Tle)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 688.99 689.64

SEN-306* H-[(D-Chg)-(D-Cha)-(D-Cha)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 729.05 730.31

SEN-307* H-[(D-Ghg)-(D-Cha)-(D-Chg)-(D-Chg)-(D-mAla)]-NH ₂ A A A B A 672.94 673.51

SEN-308* H-[(D-Trp)-(D-Trp)-(D-Chg)-(D-Cha)-(D-mPhe)]-NH ₂ A A A B A 843.07 844.29

SEN-309* Ac-[(D-Tφ)-(D-Chg)-(D-Cha)-(D-mPhθ)]-NH ₂ - A A B A 698.90 700.51

SEN-310* H-[(D-Trp)-{D-Chg)-(D-Cha)-(D-mPhe)]-NH ₂ - A A B A 656.86 658.50

SEN-311* H-[(D-Cha)-{D-Trp)-(D-Chg)-(D-Cha)-(D-mPhe)]-NH ₂ A A A B A 810.08 811.74

SEN-313* Ac-[(D-Val)-(D-lle)-{D-Leu)-(D-mLeu)]-NH ₂ - A A B A 511.70 513.47

SEN-314* H-[(D-Val)-(D-lle)-(D-Lβu)-(D-mLeu)J-NH ₂ - A A B A 469.66 471.46

SEN-317* Ac-[(D-lle)-(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)]-NH ₂ A A A B A 624.86 626.69

SEN-318* H-[(D-lle)-(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)]-NH ₂ A A A B A 582.82 584.56

SEN-319* H-[(D-l[e)-(D-Val)-(D-Leu)-(D-Leu)-(D-mLeu}J-NH ₂ A A A A 582.82 583.65

SEN-320* H-[(D-lle)-(D-Val)-(D-Leu)-(D-lle)-(D-mLeu)J-NH ₂ A A A B A 582.82 583.65

SEN-321* H-[(D-lle)-(D-Val)-(D-lle)-(D-lle)-(D-mLeu)]-NH ₂ A A A B A 582.82 583.75

Table 1(b)

Amino acid coupling method Molecularweight (Da)

Code Peptide sequence X1 X2 X3 X4 X5 Mcalc [M+H] ⁺

SEN-501* H-[(D-Ile)-(D-lle)-(D-lle)-(D-Chg)-(D-mlle)]-NH ₂ A A A B A 62289 62370

SEN-502* H-[(D-Chg)-(D-lle)-(D-lle)-(D-Chg)-(D-mlle)]-NH ₂ A A A B A 64892 64970

SEN-503* H-[(D-lle)-(D-Chg)-(D-lle)-(D-Chg)-(D-mllθ)]-NH ₂ A A A B A 64892 64960

SEN-504* H-[{D-Ghg)-(D-Chg)-(D-llβ)-(D-Chg)-(D-mllβ)]-NH ₂ A A A B A 67496 67570

SEN-505* H-[(D-lle)-{D-lle)-(D-mlle)-(D-Chg)-(D-mlle)]-NH ₂ A B A B A 63691 63770

SEN-506* H-[(D-Chg)-(D-lle)-(D-mllθ)-{D-Chg)-(D-mlle)]-NH ₂ A B A B A 66295 66370

SEN-507* H-[(D-lle)-(D-Chg)-(D-mlleHD-Chg)-(D-mlle)]-NH ₂ A B A B A 66295 66370

SEN-508* H-[(D-Chg)-(D-Chg)-(D-mll6)-(D-Chg)-(D-mlle)]-NH ₂ A B A B A 68899 68970

SEN-509* H-[(D-lle)-(D-lle)-(D-Chg)-(D-Chg)-(D-mlle)J-NH ₂ A A A B A 64892 64960

SEN-510* H-[(D-Chg)-(D-lle)-(D-Chg)-(D-Chg)-(D-mlle)]-NH ₂ A A A B A 67496 67570

SEN-511* H-[(D-lle)-(D-Chg)-(D-Chg)-(D-Chg)-(D-mlle)]-NH ₂ A A A B A 67496 67580

SEN-512* H-[(D-Chg)-(D-Chg)-(D-Chg)-(D-Chg)-(D-ml[θ)]-NH ₂ A A A B A 70100 70170

SEN-601* Ac-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLβu)]-NH ₂ A A A B A 76701 76850

SEN-602* Me-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 73900 73970

SEN-603* Me ₂ -[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 75303 75570

SEN-604* Mac-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 85212 85270

SEN-605* Mac-[(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ - A A B A 71292 71360

SEN-606* Pac-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 85015 85060

SEN-607* Pac-[(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ - A A B A 71095 71170

SEN-608* Htc-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 95725 95880

SEN-609* Htc-[(D-Tyr)-{D-Chg)-(D-Chg)-(D-mLθU)]-NH ₂ - A A B A 81806 81960

SEN-610* Tbp-[(D<;hgMI>Tyr)-(D-ChgMD-Chg)-(D-mL.eu)]-NH ₂ A A A B A 98535 98670

SEN-611* Tbp-[(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ - A A B A 84615 84670

SEN-612* H-[(D-lng)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 75899 76070

SEN-613* H-[(D-Chg)-(D-lle)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 67496 67570

SEN-614* H-[(D-Chg)-(D-Val)-(D-Chg)-(D-Chg)-(D-mLβu)]-NH ₂ A A A B A 66093 66160

SEN-615* H-[(D-Chg)-(D-Leu)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 67496 67570

SEN-616* H-[(D-Ghg)-(D-Phe)-(D-Chg)-(D-Chg)-(D-mLβu)]-NH ₂ A A A B A 70898 70970

SEN-617* H-[(D-Chg)-(D-lng)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ A A A B A 73501 73560

SEN-618* H-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NHEt A A A B A 75303 75370

SEN-619* H-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NMe ₂ A A A B A 75303 75375

SEN-620* H-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-Npyr A A A B A 77907 77982

SEN-621* H-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLβu)]-OH A A A B A 72596 72660

Table 1 (a and b) lists some of the control and test peptides which have been prepared and tested, along with some key data relating to their synthesis and characterisation:

(a) Method used for coupling each amino acid residue (A or B, as described in Example 1)

(b) M _ca | _c : calculated mass of the uncharged peptide (Da)

(c) [M+H] ⁺ : measured mass of protonated peptide (Da)

The following abbreviations are used for "non-standard" amino acids and modifying groups: mXaa is the N-methylated form of Xaa, where Xaa is the parent amino acid residue; Tie is α-terf-leucine; Chg is α-cyclohexylglycine; Cha is α- cyclohexylaianine; Ing is α-(2-indanyl)glycine; Mac is (4-morpholinyl)acetyl; Pac is (i-piperidinyl)acetyl; Htc is (S)-(-)-6-hydroxy-2,5,7,8-tetramethyl- chroman-2-carboxyl (antioxidant group of vitamin E); and Tbp is 3,5-di-t- butyl-4-hydroxyphenyl-3-propionyl (alternative antioxidant group). Only those peptide sequences which are marked with an asterisk (*) are considered to be examples of the present invention. Other peptides have been included in the table as positive or negative controls, purely for reference and comparison with the marked examples, to emphasize some of the key improvements made by the invention (for example, greater binding affinity, activity, potency and/or target-selectivity).

Example 2 - Amyloid binding affinity chromatography assays

Preparation of target peptide affinity columns Target peptide affinity columns were prepared by Fmoc-based synthesis of the following peptides (each containing a particular target amyloid-forming peptide sequence) directly onto aminopropyl-activated controlled pore glass resin (CPG, 1400 A pore size, 40 μmol/g aminopropyl substitution, 120-200 mesh): (a) AC-[KLVFFAE-GG] ₂ -NH-(CH ₂ ) _S -[CPG resin], containing the KLVFFAE target amino acid sequence of Aβ(1-42) peptide (associated with Alzheimer's disease);

(b) AC-[NFGAILS-GG] ₂ -NH-(CH ₂ MCPG resin], containing the NFGAILS target amino acid sequence of IAPP (associated with type Il diabetes);

(c) Ac-[AVVTGVTA-GG] ₂ -NH-(CH2)3-[CPG resin], containing the AWTGVTA target amino acid sequence of α-synuclein (associated with Parkinson's disease, PD);

(d) Ac-[SFYLLYYT-GG] ₂ -NH-(CH ₂ )3-[CPG resin], containing the SFYLLYYT target peptide sequence of β ₂ -microglobulin (associated with dialysis-related amyloidosis, DRA);

(e) Ac-[GVWIFYE-GG] ₂ -NH-(CH ₂ ) ₃ -[CPG resin], containing the GVWIFYE target amino acid sequence of γ-crystallin S protein (associated with cataracts). The aminopropyl-activated CPG resin was suspended in DMF (5 mL/g resin) and successive amino acid residues were added as described above for the amyloid-binding peptides (see Example 1), by repeated cycles of adding the appropriate λ/-α-Fmoc-amino acid (by coupling Method A), followed by Fmoc deprotection until the required peptide sequence was

achieved. However, the peptide was then left attached to the resin, rather than cleaved and purified.

Briefly, for each coupling step, the appropriate N-α-Fmoc-protected amino acid (3 equivalents to the resin-bound amine), 2-(1 H-benzotriazol-1-yl)- 1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU, 3eq) and 1- hydroxy-benzotriazole (HOBt, 3eq) were added to the resin in DMF (5 mL/g resin) with DIPEA (9eq). The resin was shaken at room temperature (45-60 min) and washed with DMF (2 x 5 mL/g resin, 2 min each). Provided that coupling was complete (as determined with a ninhydrin assay), the N- terminal Fmoc protecting group was removed with 20% (v/v) piperidine in

DMF (2 x 5 mL/g resin, 5 min then 20 min), and the resin washed with DMF (3 x 5 mL/g resin, 2 min each). Further cycles of coupling and deprotection were performed until the complete peptide sequence had been achieved.

Following Fmoc deprotection of the final amino acid residue, the peptidyl- resin was acetylated by treatment with acetic anhydride and pyridine (100 μl each) in DMF (5 mL/g resin) and shaken at room temperature (10 min). The resin was washed with DMF (2 x 5 mL/g resin, 2 min each) then DCM (2 x 5 mL/g resin, 2 min each), then treated with 50% TFA/DCM (3 x 5 mL/g resin, 20 min each) to remove any side chain protecting groups. Finally, the resin was washed with DCM (2 x 5 mL/g resin, 2 min each), vacuum dried, resuspended in 50% (v/v) acetonitrile (5 mL/g resin), then packed into an empty analytical HPLC column (4.6mm x 150mm).

Each affinity column was connected to an HPLC instrument and thoroughly cleaned with repeated wash cycles, each applying the following solvent gradient of 0.1 % TFA in water (buffer A) / 0.1 % TFA in acetonitrile (buffer

B), over 30 minutes, until the absorbance at 214 nm produced a steady baseline.

%A %B Time (mm) Flow (mL/min)

95 5 0 1

5 95 30 1

Measurement of relative binding affinities for alternative target peptides

Aliquots of pure test peptides (10-20 μL x 1 mM in DMSO) were injected onto alternative affinity columns comprising target amino acid sequences derived from different amyloid-forming proteins or peptides (prepared as described above). The affinity columns were pre-equilibrated with 0.1% TFA in 5% (v/v) acetonitrile/water (equivalent to 5% buffer B) before injecting each peptide. The binding affinity of the peptide for the target amino acid sequence was determined by applying the following solvent gradient of 0.1 % TFA in water (buffer A) / 0.1 % TFA in acetonitrile (buffer

B), over 30 minutes, monitoring absorbance at 214 nm.

%A %B Time (min) Flow (mL/min)

95 5 0 1

5 95 30 1

The elution profile of the peptide was normalised by subtracting that of a blank sample (10-20 μl_ DMSO alone) and the size, shape and, more importantly the position of the peak were noted. The relative binding affinity was recorded as the % acetonitrile corresponding to the top of the peak in the normalised elution profile (after subtracting the blank elution profile).

The relative binding affinities of many different amyloid-binding peptides for up to five different target amino acid sequences were determined using this method. These data are shown in Table 2 and are plotted against each other in Figure 1 (a to d), to show that some peptides are selective for one

10 specific target amino acid sequence over another, while others bind with high affinity to more than one amyloid-forming target amino acid sequence.

The binding affinity data for the KLVFFAE target peptide sequence of Aβ(1- 42) are also plotted against molecular weight of the test peptide in Figure 2(a), which shows that many small peptides (MW <750 Da) can bind to

15 Aβ(1-42) with high affinity (30-80% acetonitrile required for elution), despite their small size.

Table 2(a)

Affinity assays - % (v/v) acetonitrile 10μM A/?(1-42) assays

ThT

Code Peptide sequence Aj8(42) IAPP α-syn /?2M K-cry MTT assay assay

C1 Ac-[(L-Ser)-(L-Lys)-(L-Ser)-(Gly)-(L-Tyr)]-NH ₂ 2.8 2.3 3.0 2.7 2.3 100% 31%

C2 Ac-[(L-Tyr)-(Gly)-(L-Ser)-(L-Lys)-(L-Ser)]-NH ₂ 2.7 2.3 2.5 2.5 2.2 103% 33%

J26 Ac-[(L-Leu)-(L-Pro)-(L-Phe)-(L-Phe)-(L-Asp)]-NH ₂ 22.0 16.5 3.9 23.6 7.8 92% 32%

SEN-301* H-[(D-Chg)-(D-Cha)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 65.0 55.8 3.5 49.8 38.0 90% 42%

SEN-302* H-[(D-Cha)-(D-Chg)-(D-Chg)-(D-m_eu)]-NH ₂ 42.1 33.1 3.5 35.3 9.1 53% 30%

SEN-303* H-[(D-Cha)-(D-Gha)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 64.4 55.8 30.4 49.1 39.2 69% 54%

SEN-304* H-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 50.0 43.5 4.1 37.6 20.7 43% 59%

SEN-305* H-[(D-Chg)-(D-Cha)-(D-Tle)-(D-Chg)-(D-mLeu)]-NH ₂ 60.7 51.4 3.6 46.1 29.9 72% 51%

SEN-306* H-[(D-Chg)-(D-Cha)-(D-Cha)-(D-Chg)-(D-mLeu)]-NH ₂ 59.2 52.6 3.6 45.4 35.4 84% 44%

SEN-307* H-[(D-Chg)-(D-Cha)-(D-Chg)-(D-Chg)-(D-mAla)]-NH ₂ 52.8 45.1 3.5 - 7.5 74% 44%

SEN-308* H-[(D-Trp)-(D-Trp)-(D-Chg)-(D-Cha)-(D-mPhe)]-NH ₂ 46.4 45.4 30.9 42.1 37.6 68% 47%

SEN-309* Ac-[(D-Trp)-(D-Chg)-(D-Cha)-(D-mPhe)]-NH ₂ 52.3 46.7 29.8 47.0 40.3 61% 33%

SEN-310* H-[(D-Trp)-(D-Chg)-(D-Cha)-(D-mPhe)]-NH ₂ 34.7 35.0 7.4 34.1 24.3 76% 31%

SEN-311* H-[(D-Cha)-(D-Trp)-(D-Chg)-(D-Cha)-(D-mPhe)]-NH ₂ 48.4 46.5 27.8 42.1 36.5 85% 38%

SEN-313* Ac-[(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)]-NH ₂ 40.8 12.8 3.6 27.8 5.6 94% 33%

SEN-314* H-[(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)]-NH ₂ 4.1 2.8 2.3 4.0 2.5 95% 29%

SEN-317* Ac-[(D-lle)-(D-Val)-(D-lle)-(D-Leu )-(D-mLeu)]-NH ₂ - - - - - - 40%

SEN-318* H-[(D-lle)-(D-Val)-(D-lle)-(D-Leu)-(D-mLeu)]-NH ₂ 38.3 9.3 2.5 13.3 3.0 80% 37%

SEN-319* H-[(D-lle)-(D-Val)-(D-Leu)-(D-Leu)-(D-mLeu)]-NH ₂ 33.6 7.9 2.4 10.1 2.9 81% 34%

SEN-320* H-[(D-lle)-(D-Val)-(D-Leu)-(D-lle)-(D-mLeu)]-NH ₂ 38.1 11.4 2.4 12.6 3.0 103% 34%

SEN-321* H-[(D-lle)-(D-Val)-(D-ll8)-(D-lle)-(D-mLθu)]-NH ₂ 42.7 13.9 2.5 20.0 3.4 78% 39%

20

Table 2(b)

Affinity assays - % (v/v) acetonitrile 10μM A/?(1-42) assays

ThT MTT

Code Peptide sequence Aj8(42) IAPP σ-syn 02M K-cry assay assay

SEN-501* H-[(D-lle)-(D-lle)-(D-lle)-(D-Chg)-(D-mlle)]-NH ₂ 54 1 39 9 47 40 6 77 68% 60%

SEN-502* H-t(D-Chg)-(D-lle)-(D-lle)-(D-Chg)-(D-mlle)]-NH ₂ 58 3 45 4 46 445 154 71% 62%

SEN-503* H-[(D-lle)-(D-ChgHD-lle)-(D-Chg)-(D-mlle)]-NH ₂ 470 476 44 475 36 68% 62%

SEN-504* H-[(D-Chg)-(D-Chg)-(D-lle)-(D-ChgHD-ml!e)]-NH ₂ 65 8 52 1 4 8 50 3 31 9 69% 64%

SEN-505* H-[(D-lleHD-lleMD-mlle)-(D-ChgMD-mlle)]-NH ₂ 42 9 33 1 47 34 6 7 6 94% 42%

SEN-506* H-[(D-Chg)-(D-lle)-(D-mlle)-(D-Chg)-(D-mlle)]-NH ₂ 46 1 39 1 47 37 7 12 3 72% 45%

SEN-507* H-[(D-lle)-(D-Chg)-(D-mlle)-(D-Chg)-(D-mlIe)]-NH ₂ 46 1 38 2 45 38 1 133 75% 50%

SEN-S08* H-[(D-Chg)-(D-Ghg)-(D-mllβ)-(D-Chg)-(D-mlle)I-NH ₂ 48 6 425 4 7 404 224 67% 49%

SEN-509* H-[(D-lle)-(D-lle)-(D-Chg)-(D-Ghg)-(D-mlle)]-NH ₂ 61 8 46 9 48 474 - 56% 78%

SEN-510* H-[(D-Chg)-(D-lle)-(D-Chg)-(D-Chg)-(D-mlle)]-NH ₂ 65 7 51 2 - 50 7 34 1 57% 71%

SEN-511* H-[(D-lle)-(D-Chg)-(D-Chg)-(D-Chg)-(D-mlle)]-NH ₂ - - 46 - 35 0 71% 65%

SEN-S12* H-[(D-Chg)-(D-Ghg)-(D-Chg)-(D-Chg)-(D-mlle)]-NH ₂ - 58 3 47 56 5 40 9 70% 64%

SEN-601* Ac-[(D-Ghg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 49 3 65 5 40 9 - - 70% 101%

SEN-602* Me-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLθu)]-NH ₂ 56 0 45 8 8 3 - - 74% 81%

SEN-603* Me ₂ -[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Ghg)-(D-mLeu)]-NH ₂ 49 2 42 1 6 8 - - 69% 77%

SEN-604* Mao-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 67 0 544 28 1 - - 58% 108%

SEN-605* Mac-[(D-Tyr)-(D-Ghg)-(D-Chg)-(D-mLeu)]-NH ₂ 31 8 227 3 9 - - 109% 50%

SEN-606* Pac-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 725 559 33 0 - - 49% 104%

SEN-607* Pac-[(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 346 27 8 3 8 - - 87% 64%

SEN-608* Htc-[(D-ChgHD-TyrHD-ChgHD-Chg)-{D-mLeu)]-NH ₂ 468 61 6 429 - - 48% 76%

SEN-609* Htc-[(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 50 1 46 3 30 6 - - 85% 67%

SEN-610* Tbp-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 552 68 0 504 - - 86% 60%

SEN-611* Tbp-[(D-Tyr)-(D-Ghg)-(D-Chg)-(D-mLθu)J-NH ₂ 61 7 562 388 - - 56% 71%

SEN-612* H-[(D-lng)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 504 45 5 205 - - 61% 97%

SEN-613* H-[(D-Chg)-(D-lle)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 46 1 51 1 61 9 - - 80% 93%

SEN-614* H-[(D-Chg)-(D-Val)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 61 8 478 76 - - 61% 93%

SEN-615* H-[(D-Chg)-(D-Leu)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 60 1 49 7 170 - - 56% 99%

SEN-616* H-[(D-Chg)-(D-Phe)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 55 8 47 1 9 8 - - 62% 116%

SEN-617* H-[(D-Chg)-(D-lng)-(D-Chg)-(D-Chg)-(D-mLeu)]-NH ₂ 75 7 59 8 41 5 - - 44% 105%

SEN-618* H-[(D-Ghg)-(D-Tyr)-(D-Chg)-(D-Ghg)-(D-mLeu)]-NHEt 50 7 45 2 9 1 - - 46% 110%

SEN-619* H-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-NMe ₂ - - - - - -

SEN-620* H-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Chg)-(D-mLeu)]-Npyr - - - - - - -

SEN-621* H-[(D-Chg)-(D-Tyr)-(D-Chg)-(D-Ghg)-(D-mLeu)]-OH 48 8 43 6 8 1 - - 85% 82%

Table 2 (a and b) provides key binding affinity and activity data of peptides listed in Table 1 :

(a) Relative binding affinities of test peptides for alternative target amyloid-forming amino acid sequences attached to a solid glass resin, expressed as % (v/v) acetonitrile required for peak elution (determined using binding affinity chromatography assay as described in Example 2):

i. KLVFFAE target amino acid sequence of Aβ(1 -42) peptide (Alzheimer's disease) ii. NFGAILS target amino acid sequence of IAPP (associated with type Il diabetes) iii. AWTGVTA target amino acid sequence of α-synuclein

(Parkinson's disease, PD) iv. SFYLLYYT target amino acid sequence of β ₂ M (dialysis-related amyloidosis, DRA) v. GVWIFYE target amino acid sequence of γ-crystallin S protein (cataracts)

Experimental errors for this binding affinity assay are generally very low (below about 2%).

(b) % amyloid formed by 10 μM Aβ(1-42) in the presence of 5 μM test peptide, compared with 10 μM Aβ(1-42) alone (measured by ThT fluorescence assay, as described in Example 3). Low values (below about 100% for Aβ(1-42) alone) indicate effective inhibition of amyloid formation by the test peptide at just 5 μM (0.5:1 molar stoichiometry). Experimental errors for this assay are generally below about 10-15%.

(c) % PC12 cell viability in the presence of 10 μM Aβ(1-42) with 5 μM test peptide, compared with 100% live control cells without Aβ(1-42) and peptide (measured using the MTT assay, as described in Example 3). High values (above about 30-35% for Aβ(1-42) alone) indicate effective inhibition of amyloid toxicity by the test peptide at just 5 μM (0.5:1 stoichiometry). Experimental errors for this assay are generally below about 10-15%.

Example 3 - Amyloid aggregation and toxicity assays

Preparation of stock solutions Aβ(1-42) was prepared for amyloid aggregation and toxicity assays by dissolving the solid HCI or TFA salt of the peptide three times in TFA, and then three times in hexafluoroisopropanol (HFIP), each time with sonication and vortexing followed by drying under nitrogen. Briefly, the Aβ(1-42) HCI or TFA salt is dissolved in TFA to about 10 mg/mL with sonication and vortexing, then dried under a stream of nitrogen. This process is repeated two more times with another two aliquots of TFA. The resulting dry film of Aβ(1-42) is redissolved in HFIP to 10 mg/mL with sonication and vortexing, then again dried under nitrogen. This process is repeated two more times with another two aliquots of HFIP to ensure complete dissolution of aggregates. A 10 mM stock solution of the Aβ(1 -42) peptide in HFIP is prepared and stored at 4 ⁰ C. When required, an aliquot of this stock solution is freeze-dried and dissolved in DMSO to 200 times the required final assay concentration (e.g. 2 mM for a final assay concentration of 10 μM).

A 20 mM stock solution of each test peptide was prepared in DMSO, and aliquots of these 20 mM stock solutions were used to prepare more dilute stock solutions of each peptide in DMSO, ranging in concentration from 2 μM back up to 20 mM, for example 2 μM, 6 μM, 20 μM, 60 μM, 200 μM, 600 μM, 6 mM and 20 mM. These stock solutions were prepared and stored at 4 ⁰ C for immediate use as and when required, while the 20 mM parent stock solutions were stored frozen at -20 ⁰ C.

Preparation of amyloid aggregation plates 96-well "aggregation" plates were set up to incubate multiple amyloid aggregation experiments in parallel. Individual aggregation experiments were prepared in separate wells containing Aβ(1 -42) at a fixed concentration, with or without alternative test peptides at various concentrations, or test peptide alone as negative control (depending on the overall experiment).

Aggregation plates were prepared in 2 alternative formats. The first format was used for screening multiple test peptides in parallel against Aβ(1 -42), at fixed final assay concentrations of 5 μM and 10 μM, respectively (0.5:1 molar ratio). The second format was used for generating dose response curves for a limited number of test peptides over a range of final assay concentrations (from 0.1 to 100 μM) against a final assay concentration of 10 μM Aβ(1-42). In both formats, each experiment was repeated at least four times in separate wells.

For each experiment, a 10 μL aliquot of Aβ(1-42) in DMSO (at 200 times final concentration) was added to each well of a standard 96-well microplate. For example, to achieve a final concentration of 10 μM in each well, a 10 μL aliquot of 2 mM Aβ(1-42) in DMSO was added. Alternatively, 10 μL pure DMSO was added to produce negative controls in some wells, so that each well contained 10 μL DMSO with or without Aβ(1-42) at 200 times the required final assay concentration.

An equal volume (10 μL) of test peptide in DMSO (at 200 times the required assay concentration) was then added to each well and mixed with the 10 μL aliquot of DMSO with or without Aβ(1-42). For example, to achieve a final concentration of 10 μM in each well, a 10 μL aliquot of 2 mM test peptide in DMSO was added. Alternatively, 10 μL DMSO was added to produce further negative controls in selected wells, so that each well contained 20 μL DMSO with or without Aβ(1-42) and test peptide, each at 100 times the required final assay concentration.

Aggregation was initiated by adding 180 μl Dulbecco's PBS buffer to each well, so that each well contained 10% DMSO in 200 μl PBS buffer with or without Aβ(1-42) and/or test peptide, each at 10 times the final assay concentration. The solutions were mixed thoroughly by repeated pipetting and the plates were incubated at 37 ⁰ C. Samples were taken from each well as and when required for analysis by Thioflavin T (ThT) aggregation assays and MTT cell viability assays, as described below. Sterile conditions were maintained at all times in preparing the aggregation plates to avoid possible contamination of the MTT cell viability assays.

Thioflavin T (ThT) amyloid aggregation assays

The effect of various test peptides on amyloid formation by Aβ(1-42) was assessed by a standard amyloid aggregation assay, based on the amyloid- dependent fluorescence of the dye Thioflavin T (ThT) (LeVine and Scholten

1999).

Briefly, 20 μl_ aliquots were taken from each well of the aggregation plate (after 48 hr incubation at 37 ⁰ C) and transferred into the corresponding wells of another 96-well assay plate (solid black), each already containing 20 μM ThT in 180 μl_ Dulbecco's PBS buffer. This gave a solution with the required final concentrations of Aβ(1-42) and test peptide, 18 μM ThT and 1% DMSO in 200 μl_ PBS buffer. The plate was shaken and fluorescence was recorded using the top reader setting (10 x 1 msec), using excitation and emission filters of 440 (+ 15) and 485 (± 10) nm, respectively. Fluorescence readings from equivalent experiments were averaged and % amyloid formation was determined as follows:

% amyloid formed = F(sample) - F(blank)1 x 100%

[F(amyloid alone) - F(blank)]

Data for the ThT screening of test peptides (5 μM against 10 μM Aβ(1-42), 0.5:1 molar ratio) are shown in Table 2. Virtually all of the peptides of the present invention effectively inhibit amyloid formation at this concentration, while most of the other peptides (e.g., C1 , C2, J26, D3-R1 , D4-R1 , D5-R1 , D6-R1 ) are virtually inactive. The ThT screening data are also plotted against the binding affinity data for KLVFFAE target peptide sequence of Aβ(1-42) (from Example 2) in Figure 2(b), which shows a general correlation between activity and binding.

ThT dose response data for selected test peptides against 10 μM Aβ(1-42) are shown in Figure 3 (a and b), showing that amyloid formation is significantly inhibited by each test peptide at 10 μM (1 :1 moiar ratio).

MTT cell viability assays for amyloid toxicity

The effect of test peptides on the toxicity of Aβ(1-42) was assessed by an established cell viability assay using PC12 (rat adrenal pheochromocytoma) cells or SH-SY5Y human neuroblastoma cells, with 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) as a viability indicator

(Shearman 1999).

Briefly, 10 μL aliquots were taken from each well of a freshly prepared aggregation plate (before incubation at 37 ⁰ C), and added to the corresponding wells of a 96-well assay plate (clear bottom), each containing ~15,000 freshly plated PC12 cells in 90 μL Opti-MEM® reduced serum medium with 2 mM L-glutamine, 100 U/mL Penicillin, 100 μg/mL streptomycin and 5% foetal calf serum. Alternatively, the 10 μL aliquots from the aggregation plate were added to -30,000 freshly plated SH-SY5Y cells in 90 μL of the same medium. The assay plate was incubated in 5% CO ₂ at 37 ⁰ C for 48 hrs. Following incubation, 15 μL MTT (from Promega) was added to each well, before the plate was incubated in 5% CO ₂ at 37 ⁰ C

for another 4 hours. 100 μl_ Stop Solubilisation Solution (Promega) was added to each well and the plate was left in a sealed humidified chamber overnight at room temperature. The plate was shaken and the absorbance was recorded at both 570 nm and 650 nm. δA values were calculated by subtracting absorbance at 650 nm from absorbance at 570 nm, to reduce non-specific background absorbance. δA values from equivalent experiments were averaged and % cell viability was determined as follows:

% cell viability = FAAfsample) - δA(dead cell control)! x 100% [δA(live cell control) - δA(dead cell control)] Data for the MTT screening of test peptides (5 μM against 10 μM Aβ(1 -42),

0.5:1 molar ratio) are shown in Table 2. Virtually all of the peptides of the present invention effectively inhibit amyloid toxicity at this concentration, while most of the control peptides (e.g., C1 , C2, J26, D3-R1 , D4-R1 , D5-R1 , D6-R1 ) are virtually inactive. These MTT screening data are also plotted against binding affinity data for the KLVFFAE target peptide sequence of

Aβ(1-42) in Figure 2(c) and against the ThT screening data in Figure 2(d), snowing a general correlation between the binding and activity data obtained by three different assays.

MTT dose response data for selected test peptides against 10 μM Aβ(1-42) are shown in Figure 4 (a and b), showing that the toxicity of 10 μM Aβ(1-42) is inhibited by each test peptide at 10 μM (1 :1 molar ratio).

Example 4 - Long-term potentiation (LTP) experiments

Background

Long-term potentiation (LTP) is a natural, prolonged electrophysiological response associated with the neurological processes of learning and short- term memory, which are affected in Alzheimer's disease. Both forms of the β-amyloid peptide associated with this disease, Aβ(1-40) and Aβ(1-42), have been shown to act as potent inhibitors of LTP, and so LTP has been used as a model system for testing the efficacy of potential therapeutic agents for the disease (Walsh et al. 2002; Rowan et al. 2004).

In this example, selected test peptides were assessed for their ability to inhibit the toxic effects of Aβ(1-40) on LTP, to confirm their efficacy as potential therapeutic agents. LTP was measured along the Schaffer collaterals in rat hippocampal brain slices, as described below. Each test peptide was found to effectively block the inhibition of LTP by Aβ(1-40) at very low concentrations (down to just 1 nM peptide).

For example, the results obtained using SEN-304 (Figure 5) indicate that the toxic effect of 1 μM Aβ(1-40) on LTP is effectively blocked by SEN-304 at all 3 concentrations tested (1 μM, 10 nM and 1 nM, respectively). These results are shown for illustration only: similar data were obtained with other test peptides, demonstrating the general ability of these compounds to inhibit the toxic effects of β-amyloid peptides in a well-established model of learning and memory in Alzheimer's disease.

Sample preparation

For experiments using Aβ(1-40), the solid Aβ(1-40) HCI salt was dissolved in ddH ₂ O at 200 μM, then added to an equal volume of 2X PBS buffer to produce a solution of 100μM Aβ(1-40) in "IX PBS (180 mM NaCI, 3 mM KCI,

8 mM Na ₂ HPO ₄ and 1 mM KH ₃ PO ₄ ). When testing compounds, the Aβ(1- 40) was dissolved in ddH ₂ O at 200 μM and then added to an equal volume of 2X PBS buffer containing test peptide at twice the required concentration, producing a solution of 100μM Aβ(1-40) in 1X PBS buffer containing the appropriate concentration of test peptide. The peptides were dissolved directly into the 2X PBS buffer or, in some cases (when solubility of the peptides was limited), the peptides were dissolved initially in DMSO, before dilution to twice the required concentration with 2X PBS buffer (final concentration 5% DMSO). In control experiments, this concentration of DMSO was found to have no effect on the observed activity of Aβ(1-40) on

LTP.

Preparation and pre-treatment of brain slices

Aβ(1-40) (100μM) was incubated at 37 ⁰ C in 1 X PBS buffer for a minimum of 48 hrs prior to electrophysiological recording. All test compounds, with or without Aβ(1-40) received the same treatment. Male Wistar rats (5 - 8 weeks, 150 - 25Og) were humanely killed by cervical dislocation. Saggital hippocampal slices of 400 μm thickness were cut in cooled artificial cerebrospinal fluid (aCSF: 127 mM NaCI, 1.6 mM KCI, 1.24 mM KH ₂ PO ₄ , 1.3 mM MgSO ₄ , 2.4 mM CaCI ₂ , 26 mM NaHCO ₃ , 10 mM glucose) at below

4 ⁰ C using a microslicer (Leica VT1000S). Slices were subsequently maintained in oxygenated aCSF (95% O ₂ , 5% CO ₂ ) at room temperature for at least 1 hr before electrophysiological recordings. After this recovery period, the slices were pre-treated in small vials containing aCSF alone, or aCSF with 1 μM Aβ(1-40) with or without different test peptides at various concentrations, and incubated at 4 ⁰ C for 5 hrs.

Electrophysiological recordings

Following pre-treatment, the slices were transferred to an interface (modified 'Haas') chamber and constantly perfused with warm (30 ⁰ C), bubbled aCSF at a rate of 1.5-3.0 mL/min. The slices were perfused for at least 20 min to remove aCSF containing the test peptide before electrophysiological recordings. The Schaffer collaterals were stimulated (3-30 V, 0.03 Hz, 0.05-0.1 ms pulse width) with a concentric bipolar electrode and the evoked field excitatory postsynaptic potentials (fEPSPs) were extracellularly recorded via an Axoclamp 2A amplifier from the stratum radiatum of the CA1 region with a glass capillary microelectrode filled with 4M NaCI (resistance 2-4 Mω). Stimulation parameters were set to produce a fEPSP of 50-60% maximum amplitude. A stable fEPSP baseline was recorded over a period of at least 20 min (using Axon software, pClamp suite 8.2), before LTP was induced by high frequency stimulation (1-3 times the voltage used to generate fEPSP baseline, 100Hz frequency, 500 ms

pulse width). fEPSPs were then recorded over a further 60 min using the same stimulation parameters as for baseline.

Statistical analysis

Experiments were repeated at least 5 times using freshly prepared slices and samples. Data were averaged and significant differences were calculated using Student's t-test. Probability values of P<0.05 were considered to represent significant differences.

Example 5 - SAR analysis and molecular modelling

Analysis of structure-activity relationships

Successive rounds of synthetic combinatorial peptide libraries were designed and prepared so that alternative pairs of peptides in each peptide library differed only by single, well-defined structural modifications throughout the whole peptide molecule. The peptide libraries were designed in this way so that any differences between the binding affinity, activity or any other important properties of such related peptides could be measured and then unambiguously associated with a single, well-defined structural modification.

In one peptide library for example, the first amino acid side chain of a particular peptide sequence was modified to many alternative side chains having a wide range of characteristics, including but not limited to:

(d) size: small, medium or large (related to the number of carbon atoms); (e) shape: straight-chain, branched or cyclic (related to connectivity of non-hydrogen atoms);

(f) flexibility: rigid or flexible (related to number of rotatable bonds);

(g) hydrophobic and hydrophilic (related to number of hydrogen bond donors and acceptors); (h) aromatic or aliphatic (whether or not side chain contains an aromatic ring); and

(i) origin: natural or non-natural (whether or not side chain is that of a natural amino acid).

The peptides were synthesised (as described in Example 1 ) and tested for the following:

(a) binding to various target amino acid sequences, as described in Example 2;

(b) ability to inhibit amyloid formation and toxicity, using the ThT aggregation and MTT cell viability assays as described in Example 3; (c) overall solubility in water and PBS buffer; and

(d) logD value (standard measurement of partition between octanol and water, as indicator of potential bioavailability in vivo).

By comparing the above experimental data derived for each peptide with the characteristics of its modified side chain, it was found that the first amino acid side chain in the peptide sequence had the following generally preferred characteristics (provided other characteristics were more or less maintained):

(a) medium and large side chains were generally preferred over small side chains;

(b) cyclic side chains were generally preferred over branched side chains, which were generally preferred over unbranched side chains; (c) rigid side chains were generally preferred over flexible side chains;

(d) hydrophobic side chains were generally preferred over hydrophilic side chains;

(e) aliphatic side chains were generally preferred over aromatic side chains; and (f) non-natural side chains were generally preferred over natural side chains;

For example, cyclohexylglycine (whose side chain has all of these characteristics) was found to be particularly favoured, however other hydrophobic residues such as indanylglycine were also found to have highly favoured side chains.

In a second peptide library, the second amino acid side chain in the peptide sequence was modified to the same selection of alternative side chains as included in the first peptide library above. Again, by testing each peptide for binding affinity, activity and various other properties, it was found that the second amino acid side chain in the peptide generally had the same preferred characteristics as the first side chain. In fact, in three further peptide libraries, it was discovered that each of the next three amino acid side chains had the same preferred characteristics as the first side chain indicated above (providing other characteristics were more or less maintained), regardless of their relative position in the amino acid sequence. This finding was particularly surprising given that all known peptide-based inhibitors of amyloid formation consist of highly heterogeneous peptide sequences comprising a number of different amino acid residues in a specific order. In a further peptide library, it was found that α-D-amino acid residues were generally preferred at each position in the peptide sequence over α-L-amino acid residues, not just in terms of biological stability (as would be expected), but also in terms of their binding affinity and activity.

Subsequent peptide libraries revealed further generally preferred structural features. For example, while N-methylation of any residue in the peptide was generally found to improve the solubility of the peptide (apart from the N-terminus), N-methylation of only the last residue in the peptide (X5) was (generally) found to have a more beneficial effect on both binding affinity and activity than N-methylation of any other residue. Some of the preferred structural features identified above are apparent even from the very limited number of examples provided in Tables 1 and 2.

Further work demonstrated that some of the identified preferred structural features could generally be combined to produce completely novel and highly preferred peptide sequences. Some of these peptide sequences are included towards to bottom of Tables 1 and 2, for example.

SAR-guided molecular modelling

Based on those structure-activity relationships identified as described above, molecular modelling was used as a tool to understand the molecular basis for the generally preferred structural features which were identified. For example, SEN-606 was found to have one of the highest binding affinities for the KLVFFAE target amino acid sequence of Aβ(1-42), requiring as much as 72.5% acetonitrile for elution from the Aβ(42) affinity column only at (see Table 1 ). A molecular model was therefore created of the KLVFFAE target amino acid sequence as a symmetric two-stranded antiparallel β-sheet, since it had been shown that this peptide aggregates into β-sheets by self association of β-strands in vitro. Close inspection of the model revealed a potential binding site along the edge of each β-strand, as shown in Figures 6(a) and 6(c), viewed from opposite sides of the two- stranded β-sheet. A molecular model of SEN-606 was then created and various modes of interaction with the target β-strand were explored. In one specific model, shown in Figures 6(b) and 6(d), SEN-606 forms a surface which is perfectly complementary to the potential binding site along the edge of the target β- strand. In particular: SEN-606 forms and extended β-strand, which forms a 3-stranded β-sheet (in the optimum antiparallel orientation) with the two- stranded target β-sheet; its extended peptide backbone forms 5 hydrogen bonds with the peptide backbone of the target β-strand; and all six of its hydrophobic side chains (including its N-terminal piperidinyl ring) are tightly packed together, with optimum torsional geometry, to form a compact hydrophobic core with the hydrophobic side chains of the target β-strand on either side of the three-stranded β-sheet.

The proposed binding surface of SEN-606 is shown more clearly in Figure 6(e), where favourable packing of its hydrophobic cyclic aliphatic side chains with each other and with its central phenol (tyrosine) side chain is most apparent.

The key general features of this proposed binding surface which may explain the particularly high binding affinity of SEN-606 for the target KLVFFAE target amino acid sequence of Aβ(1-42) (as well as to other amyloid-forming target amino acid sequences) are indicated in Figure 6(f). Further molecular modelling work was performed with other examples of amyloid-binding peptide sequences of the present invention. In each case, a general correlation was observed between the measured binding affinity of the the peptide for the target amino acid sequence, and the degree of complementarity between potential binding surfaces. Moreover, the molecular modelling work appeared to support all of the experimentally determined preferred structural features described above.

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