The present disclosure relates to hybrid polypeptides acting as dual GHSR and NPY5R agonists. In particular, the present disclosure relates to hybrid peptides comprising an analogue of an hGhrelin N- terminal fragment covalently linked to an analogue of hNPY or an analogue of a hNPY C-terminal fragment. The disclosure further relates to the medical use of such hybrid polypeptides in the treatment of cachexia and/or anorexia.

BACKGROUND

Cachexia is a complex syndrome associated with an underlying illness causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. It is estimated that Cachexia affects 6-12 million individuals in Europe, the US, and Japan alone.

Cachexia is characterized by an unintended weight loss resulting in an overall lowered quality of life and an increased mortality leading to a total of 1.5-2.0 million deaths per year. A range of diseases may cause cachexia, most commonly cancer, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), and AIDS. Systemic inflammation from these conditions can cause detrimental changes to metabolism and body composition leading to cachexia. It is estimated that cancer cachexia causes 20-30% deaths of cancer patients globally and that COPD cachexia is associated with approximately a 50% reduction in median survival. Thus, there is a need in the art for effective treatments of cachexia.

Human Ghrelin (hGHR) is an octanoylated peptide hormone with the amino acid sequence GS(n-octanoyl- S)FLSPEHQRVQQRKESKKPPAKLQPR. hGHR is produced by enteroendocrine cells of the gastrointestinal tract and is primarily secreted from the gut prior to a meal. hGHR is often referred to as "hunger hormone" because it increases food intake and plays an important role in regulating the complex process of energy homeostasis. hGHR adjusts both energy input - by adjusting hunger signals - and energy output - by adjusting the proportion of energy going to ATP production, fat storage, glycogen storage, and short-term heat loss. hGHR activates cells in the anterior pituitary gland and hypothalamic arcuate nucleus (ARC) via the gastric vagal afferent nerve and circumventricular organs by triggering the growth hormone secretagogue receptor (GHSR). These receptors are present in e.g., neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons. Once activated, theses neurons produce and release y-aminobutyric acid (GABA) which inhibits anorectic proopiomelanocortin (POMC) neurons, decreasing the release of the anorectic peptide o- melanocyte-stimulating hormone (o-MSH). This effectively reduces the quantity of o-MSH capable of binding to satiety promoting melanocortin 4 receptors (MC4Rs). Concurrently, activated NPY/AgRP neurons increase their production and secretion of the orexigenic (appetite stimulating) peptides hNPY and AgRP. The reduction in the anorectic peptide o-MSH and the enhancement of orexigenic peptides NPY and AgRP together reduce the activity of second order anorexigenic neurons in the paraventricular nucleus (PVN), which promotes homeostatic feeding behaviours. Furthermore, the binding of hGHR to GHSR in pituitary cells also stimulates the secretion of growth hormone (GH) by the pituitary gland causing an anti-catabolic action on muscle tissue which promotes an increase in muscle mass. Finally, hGHR also stimulates VTA dopamine (DA) neurons increasing the frequency and probability of DA release from their projections in the nucleus accumbens (NA), prefrontal cortex (PFC), hippocampus (HIP), and amygdala (AMY) to encourage mesolimbic reward feeding.

Human neuropeptide Y (hNPY) is a 36 amino acid peptide hormone with the amino acid sequence YPSKPDNPGEDAPAEDMARYYSALRHYINLTTRQRY. hNPY is an abundant neuropeptide of the hypothalamus, and one of the most potent orexigenic factors. hNPY acts upon the NPY receptors designated NPYIR (YI), NPY2R (Y2), NPY4R (Y4), and NPY5R (Y5). This receptor family belongs to a class of G protein- coupled receptors (GPCRs) and is expressed in the CNS, especially in regions of the hypothalamus. The receptors NPY1-NPY5 exhibit both anorectic (NPY2, NPY4) and orexigenic effects (NPY5, NPY1) and are activated by the endogenous peptide hormones hNPY, hPYY, and hPP. hGHR analogues, acting as GHSR agonists, are known from the prior art (see e.g., WO 2016/065042). In addition a selective Y5 receptor agonist (Y5Ra) (i.e. [cPPl-7,NPY19-23,Ala31,Aib32,Gln34]-hPP) has been described in the prior art (Cabrele C., et al. J. Biol. Chem, 2000, 275 (46), pp. 36043-36048.). However, currently, no dual acting polypeptides targeting both GHSR and NPY5R have been described.

In view of the orexigenic effects associated with targeting NPY5R and GHSR, future treatments for cachexia might benefit from a hybrid polypeptide agonizing both GHSR and NPY5R. The present invention sets out to solve the problem of providing polypeptides targeting both GHSR and NPY5R in order to provide improved treatments of cachexia.

SUMMARY

Hybrid polypeptides are highly desirable compared to combination therapy with individual polypeptides for a number of reasons. First, hybrid polypeptides are easier to formulate into a single dosing unit as compared to mixtures of different polypeptides. This is primarily due to the fact that different peptides may possess different physiochemical properties, e.g., isoelectric point, solubility, or chemical stability at a given pH, which means that one formulation developed for one polypeptide may be less optimal for or incompatible with a different polypeptide. Therefore, combination therapy with individual polypeptides may require individual dosing units. Secondly, hybrid polypeptides are cheaper to manufacture compared to individual polypeptides and also reduce the burden of regulatory approval. It is therefore an object of the present invention to provide a hybrid polypeptide that agonizes GHSR and NPY5R. It is another object of the present invention to provide an improved therapy for the treatment of cachexia and/or anorexia, in particular cachexia.

The inventors found that these objects could be achieved by covalently linking an analogue of an hGhrelin N-terminal fragment consisting of 8-18 amino acids with an analogue of hNPY or an analogue of a hNPY C-terminal fragment consisting of 18-36 amino acids.

Thus, in a first aspect the present disclosure relates to a polypeptide comprising the structure of Formula (I)

Z1-Z2 (I), wherein

Z1 comprises an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 8-18 amino acids (i.e. Xi-Xs to Xi-Xis using the numbering of hGhrelin) and comprising the amino acid sequence Xi-X2-[Dpr*]- X4-L-S-P-X8, wherein Xi is selected as P, G, NMeGly, NMePro, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha; or is a derivate thereof having 1 amino acid substitution;

* denotes a C8 (i.e. octanoyl) or CIO (i.e. decanoyl) lipid;

Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 18-36 amino acids (i.e. X19-36 to Xi-36 using the numbering of hNPY) and comprising the amino acid sequence R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or is a derivate thereof having 1-2 amino acid substitution(s); and wherein the C-terminal of Z1 is covalently linked to the N-terminal of Z2 through an amide bond.

In a second aspect, the present disclosure relates to a polypeptide according to the first aspect for use as a medicament.

DEFINITIONS AND ABBREVIATIONS

According to the present invention, unless otherwise stated, the amino acids are all L-amino acids (L- stereoisomer, natural amino acids). In the present context, substitutions in an analogue/derivative may be substitutions to natural amino acids as well as unnatural amino acids, including L- and D-stereoisomers. Preferably, a substitution in a variant is a conservative substitution to a conservative amino acid. The groups of conservative amino acids may be defined as:

G, A, V, L, I, P (aliphatic or cyclic),

S, C, T, M (hydroxyl or sulphur containing)

F, Y, W (aromatic)

H, K, R (basic)

D, E, N, Q (acidic or amide)

NMeG denotes the amino acid methylglycine (also referred to as N-Methylglycine, NMeGly, MeGly or sarcosine) with the structure: methylglycine

NMeP denotes the amino acid methyl-L-proline (also referred to as N-Methyl-L-proline, NMePro or (S)-l- methylpyrrolidine-2-carboxylic acid) with the structure: methyl-L-proline

Dpr denotes the amino acid (S)-2,3-diaminopropionic acid (also referred to as L-2,3-diaminopropionic acid) with the structure:

(S)-2,3-diaminopropanoic acid

Aib denotes the amino acid 2-amino-2-methylpropanoic acid (also referred to as 2-aminoisobutyric acid) with the structure:

2-amino-2-methylpropanoic acid

NMeQ denotes the amino acid N-methyl-L-glutamine (also referred to as N-Methylglutamine, NMeGIn, or MeGIn) with the structure:

N-methyl-L-glutamine

NMeAla denotes the amino acid N-methyl-L-alanine (also referred to as N-Methylalanine, NMeA, or MeAla) with the structure:

N-methyl-L-alanine

Cha denotes the amino acid (S)-2-amino-3-cyclohexylpropanoic acid (also referred to as L- cyclohexylalanine) with the structure:

(S)-2-amino-3-cyclohexylpropanoic acid

Tie denotes the amino acid (S)-2-amino-3,3-dimethylbutanoic acid (also referred to as L-2-(tert- butyl)glycine) with the structure:

(S)-2-amino-3,3-dimethylbutanoic acid

1-Nal denotes the amino acid (S)-2-amino-3-(naphthalen-l-yl)propanoic acid (also referred to as 3-(l- napthyl)-L-alanine) with the structure:

(S)-2-amino-3-(naphthalen-1 -yl)propanoic acid

Pip denotes the amino acid (S)-piperidine-2-carboxylic acid (also referred to as L-pipecolic acid) with the structure:

(S)-piperidine-2-carboxylic acid

Nip denotes the amino acid (S)-piperidine-3-carboxylic acid (also referred to as L-nipecotic acid) with the structure:

(S)-piperidine-3-carboxylic acid Nle denotes the amino acid (2S)-2-aminohexanoic acid (also referred to as L-norleucine)

(S)-2-aminohexanoic acid

Phe(4F) denotes the amino acid (S)-2-amino-3-(4-fluorophenyl)propanoic acid (also referred to as 4-fluoro-

L-phenylalanine)

(S)-2-amino-3-(4-fluorophenyl)propanoic acid i R or (psi)R denotes the amino acid arginine, wherein the amide bond formed between the carboxylic acid of the arginine and the amino group in the next amino acid is reduced to a secondary amine as illustrated below.

Arginine residue Reduced arginine residue According to the present invention, ECso values are used as a measure of agonist potency at a given receptor. An ECso value is a measure of the concentration of a compound required to achieve half of that compound's maximal activity in a particular assay. It is well known that ECso values depend on the assay type and assay conditions. Furthermore, variation may also be present within the same assay under apparently identical assay conditions due to variation in e.g. receptor expression in the cells (i.e. receptor density). Thus, in order to compare ECso values between different assay runs, hGhrelin and hNPY were used as internal standards for the GHSR and the NPY5R (Y5), respectively. Thus, the GHSR ECso of the polypeptides is expressed as a relative GHSR ECso compared to hGhrelin (see Table 1). Likewise, the NPY5R (Y5) ECso is expressed as a relative ECso compared to hNPY (see Table 2). The polypeptides according to the invention have a relative GHSR ECso < 300 and a relative NPY5R ECso < 200, preferably a relative GHSR ECso < 250 and a relative NPY5R ECso < 150, more preferably a relative GHSR ECso < 200 and a relative NPY5R ECso < 100, most preferably a relative GHSR ECso < 100 and a relative NPY5R ECso < 50.

According to the present invention, a polypeptide or a derivative thereof may be lipidated, in addition to the octanoyl (C8) or decanoyl (CIO) present on Dpr (i.e. X3 in Zl). Preferably, any additional lipidation is performed on Z2. Thus, when the present disclosure refers to Z2 being an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 18-36 amino acids, this does not exclude the presence of any lipids linked to any of the 18-36 amino acids. Preferably, the lipidation is performed by introducing a lysine (K) residue in one of 18-36 amino acids of Z2 to which the lipid can be attached. Preferably, the lipid is selected from the list consisting of C18DA[yE][OEG][OEG]-, C18DA[yE][eLys]-, C18DA[yE][eLys][eLys]-, C18DA[ACHC][yE][OEG][OEG],C18DA[yE][bAla]-, C18DA[yE][yE]-, C18DA[yE][Ahx]-, C18DA[yE][OEG][OEG][OEG][OEG][OEG][OEG]-, C18DA[yE][OEG][OEG][OEG]-, [OEG][eLys]-, C18DA[yE][OEG][OEG][eLys]-, C20DA[yE]-, C20DA[yE][OEG][OEG]-, C20DA[yE][OEG][OEG][eLys]-, C20DA[yE][OEG][OEG][OEG][OEG]-, and C20DA[yE][yE][OEG][OEG]-. Preferably, the lipidation is performed in one of the positions X4, Xe-7,X9 -13, X15-23 of Z2 as illustrated herein.

According to the present invention, a polypeptide or a derivative thereof may be in the form of a pharmaceutically acceptable salt. Thus, pharmaceutically acceptable salts are intended to include any salts that are commonly used in formulations of peptides. Such salts include both acid addition salts and basic salts, and examples may be found in e.g., Remington's pharmaceutical sciences, 17 ^th edition. Likewise, a polypeptide or a pharmaceutically acceptable salt may be in the form of a solvate (e.g., a hydrate).

DETAILED DESCRIPTION

The present invention relates to a group of hybrid polypeptides comprising the general structure of Z1-Z2. Zl is an analogue of a hGhrelin N-terminal fragment and provides the hybrid polypeptide with GHSR activity. Z2 is an analogue of hNPY or an analogue of an hNPY C-terminal fragment and provides the hybrid polypeptide with NPY5R activity. Thus, the present invention relates to the surprising finding that dual acting GHSR agonists (GHSRa) and NPY5R agonists (NPY5Ra) can be provided by linking certain N-terminal fragments derived from analogues of hGhrelin with certain C-terminal fragments derived from analogues of hNPY. More particularly, the present invention relates to the surprising finding that an analogue of a hGhrelin N-terminal fragment consisting of merely 8 amino acids was sufficient to provide hybrid polypeptide having GHSR activity. Likewise, an analogue of an hNPY C-terminal fragment consisting of merely 18 amino acids was sufficient to provide hybrid polypeptide having NPY5R activity.

Tables 1 and 2 in conjunction exemplify the amino acid sequences of the hybrid polypeptides according to the invention. As can be seen from Tables 1 and 2, 175 hybrid polypeptides were systematically designed, synthesized, and tested. Table 1 shows the amino acid sequences of Z1 in the hybrid polypeptide of general Formula Z1-Z2, wherein position Xi, is the N-terminal amino acid of the hybrid polypeptides. Table 2 shows the amino acid sequences of Z2 in the hybrid polypeptides of the general Formula Z1-Z2, wherein position X36, is the C-terminal amino acid of the hybrid polypeptides.

From Table 1, it can be seen that Z1 may consist of 8 to 18 amino acids (see Table 1, last row) and comprises the amino acid sequence Xi-X2-[Dpr*]-X4-L-S-P-Xs. Furthermore, Table 1 summarizes the amino acids tested (see Table 1, second last row) in Z1 capable of providing the hybrid polypeptides with GHSR activity. The exemplified length of Z1 (Table 1, last row) and the exemplified amino acids (Table 1, second last row) are reflected in the claimed subject matter.

From Table 2, it can be seen that Z2 may consist of 18 to 36 amino acids (see Table 2, last row) and comprises the amino acid sequence R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36. Furthermore, Table 2 summarizes the amino acids tested (see Table 2, second last row) in Z2 capable of providing the hybrid polypeptides with NPY5R activity. The exemplified length of Z2 (Table 2, last row) and the exemplified amino acids (Table 2, second last row) are reflected in the claimed subject matter.

Thus, in a first aspect the present disclosure relates to a polypeptide comprising the structure of Formula (I)

Z1-Z2 (I), wherein

Z1 comprises an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 8-18 amino acids (i.e. Xi-Xs to Xi-Xis using the numbering of hGhrelin) and comprising the amino acid sequence Xi-X2-[Dpr*]- X4-L-S-P-X8, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha; or is a derivate thereof having 1 amino acid substitution;

* denotes a C8 (i.e. octanoyl) or CIO (i.e. decanoyl) lipid;

Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 18-36 amino acids (i.e. X19-36 to Xi-36 using the numbering of hNPY) and comprising the amino acid sequence R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, M, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34is selected as Q, NMeAla, NMeQ, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; Xse is selected as Y, Phe(4F), or Cha; or is a derivate thereof having 1-2 amino acid substitution(s); and wherein the C-terminal of Z1 is covalently linked to the N-terminal of Z2 through an amide bond.

Structure-activitv-relationship (SAR)

Table 1 in conjunction with Table 2 summarize the SAR for the hybrid polypeptides of formula Z1-Z2. Table 1 shows the amino acid sequence of Z1 and the relative ECso on the GHSR compared to hGhrelin (the endogenous ligand for GHSR). Table 2 shows the amino acid sequence of Z2 and the relative ECso on NPY5R compared to hNPY (the endogenous ligand for NPY5R (Y5)). As can be seen, some of the best hybrid polypeptides are more or less equipotent, or even more potent than the native peptides hGhrelin and hNPY. A majority of the peptides were found to be less potent than the native peptides hGhrelin and hNPY, as the merging of a hGhrelin part (Zl) and a hNPY part (Z2) to some extent represents a tradeoff between GHSR activity and NPY5R activity. However, a drop in potency may be adjusted by e.g. increasing the dosing amount or dosing frequency. Furthermore, potency cannot be directly correlated with in vivo efficacy as many other factors must be considered, such as bioavailability, volume of distribution, half-life, and target exposure.

Zl (i.e. N-terminal fragment)

Table 1, last column, summarizes the exemplified length of Zl in the hybrid polypeptides, and Table 1, second last column, summarizes the exemplified amino acids present in Zl in the hybrid polypeptides. In the SAR 1, the length of Zl was initially tested. SEQ ID NO: 9-14 was synthesized by varying the length of the amino acid sequence of Zl from 8 to 18 amino acids while keeping Z2 constant. As can be seen from the SAR in Table 1, an amino acid length of Zl from 8 to 18 amino acids provided hybrid polypeptides with a relative GHSR ECso of 4.3-13.

Thus, the inventors found that Zl may comprise an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 8-18 amino acids and comprising the amino acid sequence Xi-X2-[Dpr*]-X4-L-S-P- Xs, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha in order to obtain GHSR activity.

The present SAR suggests that it is most preferred when Zl comprises an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 15 amino acids, second most preferred when said analogue consists of 9-14 or 16 amino acids, third most preferred when said analogue consists of 17 amino acids, fourth most preferred when said analogue consists of 18 amino acids, and least preferred when said analogue consists of 8 amino acids. The SAR further shows that Zl should at least comprise the amino acid sequence X1-X2- [Dpr*]-X4-L-S-P-X ₈ . Thus, in a preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 9-18 amino acids and comprises Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A.

In a more preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 9-17 amino acids and comprising Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A.

In an even more preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 9-16 amino acids and comprising Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A.

In yet an even more preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 10-16 amino acids and comprising Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9-Xio, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1- Nal; Xs is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A; X10 is selected as Q, S, or Aib.

In yet an even more preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 11-16 amino acids and comprising Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9-Xio-Xn, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A; X10 is selected as Q, S, or Aib; Xu is selected as R or K.

In yet an even more preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 12-16 amino acids and comprising Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9-Xio-Xn-Xi2, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A; X10 is selected as Q, S, or Aib; Xu is selected as R or K; X12 is selected as V or A.

In yet an even more preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 13-16 amino acids and comprising Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9-Xio-Xn-Xi2-Xi3, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A; X10 is selected as Q, S, or Aib; Xu is selected as R or K; X12 is selected as V or A; X13 is selected as Q or S. In yet an even more preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 14-16 amino acids and comprising Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3- X14, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib or A; X10 is selected as

Q, S, or Aib; Xu is selected as R, or K; X12 is selected as V, or A; X13 is selected as Q, or S; X14 is selected as Y, S, or Q.

In the most preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, said analogue consisting of 15 amino acids having the sequence Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-

R, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A; X10 is selected as Q, S, or Aib; Xu is selected as R or K; X12 is selected as V or A; X13 is selected as Q or S; X14 is selected as Y, S, or Q.

In another embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue is selected from the list consisting of: Xi-X2-[Dpr*]-X4-L-S-P-Xs, Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9, Xi- X2-[Dpr*]-X4-L-S-P-X ₈ -X9-Xio, Xi-X2-[Dpr*]-X4-L-S-P-X8-X ₉ -Xio-Xn, Xi-X ₂ -[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2, Xi-X2-[Dpr*]-X4-L-S-P-X ₈ -X9-Xio-Xii- X12-X13, Xi-X2-[Dpr*]-X4-L-S-P-X8-X ₉ -Xio-Xn- X12-X13-X14, Xi-X ₂ -[Dpr*]- X4-L-S-P-X8-X9-X10-X11-X12-X13-X14-R, Xi-X2-[Dpr*]-X4-L-S-P-X ₈ -X9-Xio-Xn-Xi2-Xi3-Xi4-R-K, Xi-X ₂ -[Dpr*]-X4- L-S-P-X8-X9-X10-X11-X12-X13-X14-R-K-E, or Xi-X2-[Dpr*]-X4-L-S-P-X ₈ -X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E-S, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A; X10 is selected as Q, S, or Aib; Xu is selected as R or K; X12 is selected as V or A; X13 is selected as Q or S; X14 is selected as Y, S, or Q; or Z1 is derivative of any such sequence having 1 amino acid substitution.

In a preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue is selected from the list consisting of: Xi-X2-[Dpr*]-X4-L-S-P-Xs-H, Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9- X10, Xi-X2-[Dpr*]-X4-L-S-P-X ₈ -X9-Xio-Xn, Xi-X ₂ -[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2, Xi-X ₂ -[Dpr*]-X4-L-S-P-X ₈ - X9-X10-X11-X12-X13, Xi-X2-[Dpr*]-X4-L-S-P-X ₈ -X9-Xio-Xii- X12-X13-X14, Xi-X ₂ -[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2- [Dpr*]-X4-L-S-P-X8-X ₉ -Xio-Xii-Xi2-Xi3- wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X4 is selected as F or 1-Nal; Xs is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A; X10 is selected as Q, S, or Aib; Xu is selected as R or K; X12 is selected as V or A; X13 is selected as Q or S; X14 is selected as Y, S, or Q; or is a derivative thereof having 1 amino acid substitution.

In another preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue is selected from the list consisting of: Xi-X2-[Dpr*]-X4-L-S-P-Xs-H, Xi-X2-[Dpr*]-X4-L-S-P-Xs- X ₉ -Xio, Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9-Xio-Xn, Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9-Xio-Xn-Xi2, Xi-X ₂ -[Dpr*]-X4-L-S-P- X12-X13-X14-R-K-E, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X is selected as F or 1-Nal; X ₈ is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A; X10 is selected as Q, S, or Aib; Xu is selected as R or K; X12 is selected as V or A; X13 is selected as Q, or S; Xw is selected as Y, S, or Q; or is a derivative thereof having 1 amino acid substitution.

In another preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue is selected from the list consisting of: Xi-X2-[Dpr*]-X4-L-S-P-X ₈ -Xg, Xi-X2-[Dpr*]-X4-L-S-P-X ₈ - X9-X10, Xi-X ₂ -[Dpr*]-X4-L-S-P-X ₈ -X9-Xio-Xn, Xi-X ₂ -[Dpr*]-X -L-S-P-X ₈ -X9-Xio-Xn-Xi2, Xi-X ₂ -[Dpr*]-X4-L-S-P- X ₈ -X9-X1O-X11-X12-X13, Xi-X ₂ -[Dpr*]-X4-L-S-P-X ₈ -X9-Xio-Xn-Xi2-Xi3-Xi4, Xi-X ₂ -[Dpr*]-X4-L-S-P-X ₈ -X9-Xio-Xn- X12-X13-X14-R, or Xi-X ₂ -[Dpr*]-X4-L-S-P-X ₈ - X9-X10-X11-X12-X13-X14-R-K, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X is selected as F or 1-Nal; X ₈ is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A; X10 is selected as Q, S, or Aib; Xu is selected as R or K; X12 is selected as V or A; X13 is selected as Q or S; X1 is selected as Y, S, or Q; or is a derivative thereof having 1 amino acid substitution.

In the most preferred embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue is selected as Xi-X2-[Dpr*]-X -L-S-P-X ₈ -X9-Xio-Xn-Xi2-Xi3-Xi4-R, wherein Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X is selected as F or 1-Nal; X ₈ is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A; X10 is selected as Q, S, or Aib; Xu is selected as R or K; X12 is selected as V or A; X13 is selected as Q or S; Xw is selected as Y, S, or Q; or is a derivative thereof having 1 amino acid substitution.

In any of the above-mentioned embodiments described for Z1 the amino acids are selected as follows: Xi is selected as P, G, NMeP, NMeG, Nip, or Pip; X2 is selected as S, T, V, Aib, or Tie; X is selected as F or 1- Nal; X ₈ is selected as Y, R, E, F, or Cha; X9 is selected as H, Aib, or A; X10 is selected as Q, S, or Aib; Xu is selected as R or K; X12 is selected as V or A; X13 is selected as Q or S; X1 is selected as Y, S, or Q; or Z1 is derivative of any such sequence having 1 amino acid substitution.

Preferably, Xi in Z1 is selected as P (1), G (2), NMeP (3), NMeG (4), Nip (5), or Pip (6), wherein (1) is the most preferred and (6) the least preferred amino acid.

Preferably, X2 in Z1 is selected as S (1), T (2), V (3), Aib (4), or Tie (5), wherein (1) is the most preferred and (5) the least preferred amino acid. Preferably, X4 in Z1 is selected as F (1) or 1-Nal (2), wherein (1) is the most preferred and (2) the least preferred amino acid.

Preferably, Xs in Z1 is selected as Y (1), R (2), E (3), F (4), or Cha (5), wherein (1) is the most preferred and (5) the least preferred amino acid.

Preferably, X9 in Z1 is selected as H (1), Aib (2), or A (3), wherein (1) is the most preferred and (3) the least preferred amino acid.

Preferably, X10 in Z1 is selected as Q (1), S (2), or Aib (3), wherein (1) is the most preferred and (3) the least preferred amino acid.

Preferably, Xu in Z1 is selected as R (1), or K (2), wherein (1) is the most preferred and (2) the least preferred amino acid.

Preferably, X13 in Z1 is selected as Q (1), or S (2), wherein (1) is the most preferred and (2) the least preferred amino acid.

Preferably, Xw in Z1 is selected as Y (1), S (3) or Q (2), wherein (1) is the most preferred and (3) the least preferred amino acid.

Z2 (i. e. C-terminai fragment of hybrid polypeptide)

In the first SAR (i.e. SAR 1), the length of Z2 was initially examined. SEQ ID NO: 1-8 and 14-15 were synthesized by varying the length of the amino acid sequence of Z2 from 18 to 33 amino acids while keeping Z1 constant. As can be seen from the SAR, an amino acid length of Z2 from 18 to 33 amino acids provided hybrid polypeptides with a relative NPY5R ECso of 3.0-18. Table 2, last column, summarizes the exemplified length of Z2 in the hybrid polypeptides, and Table 2, second last column, summarizes the exemplified amino acids present in Z2 in the hybrid polypeptides.

Thus, the inventors found that Z2 may comprise an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 18-36 amino acids and comprising the amino acid sequence R-Y-Y- S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein X26 is selected as R or H; X27 is selected as Y, or Cha; X30 is selected as W, L, M, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha in order to obtain NPY5R activity.

The SAR suggests that the hybrid peptides performed better in terms of relative GHSR and NPY5R potency, when the amino acid sequence of Z2 was increased in length from 18 amino acids (i.e. R-Y-Y-S-A-L-R-X26- X27-I-N-X30-X31-X32-R-X34-X35-X36) up to and including 34 amino acids (i.e. S-X4-P-X6-X7-P-G-X10-N-A-T-P-E- X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X3 6).

Thus, in an embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 19-36 amino acids and comprising A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, wherein X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, M, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D- Gln, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha.

In a preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 20-36 amino acids and comprising X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, and wherein X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, M, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha.

In a more preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 21-36 amino acids and comprising X16-X17-A-R-Y-Y-S-A-L-R-X26-X27- I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, M, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha.

In an even more preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C- terminal fragment, said analogue consisting of 22-36 amino acids and comprising E-X16-X17-A-R-Y-Y-S-A-L- R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, M, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha.

In an yet even more preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 23-36 amino acids and comprising P-E-X16-X17-A-R-Y-Y-S- A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha. In a highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 24-36 amino acids and comprising T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi6 is selected as E, Q, D, N, or K; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, M, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha.

In a more highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C- terminal fragment, said analogue consisting of 25-36 amino acids and comprising A-T-P-E-X16-X17-A-R-Y- Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, M, or Nle; X31 is selected as A, or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha.

In an even more highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 26-36 amino acids and comprising N-A-T-P-E-Xie- X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D- Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha.

In yet an even more highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 27-36 amino acids and comprising X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, wherein X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R, or H; X27 is selected as Y, or Cha; X30 is selected as W, L, or Nle; X31 is selected as A, or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; Xse is selected as Y, Phe(4F), or Cha.

In yet an even more highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 28-36 amino acids and comprising G-X10-N-A-T- P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X3 5-X36, wherein X10 is selected as D, E, or K; Xi ₆ is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y, or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; Xse is selected as Y, Phe(4F), or Cha. In yet an even more highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 29-36 amino acids and comprising P-G-Xio-N-A- T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, wherein X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; Xse is selected as Y, Phe(4F), or Cha.

In yet an even more highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 30-36 amino acids and comprising X7-P-G-X10-N- A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X3 4-X35-X36, wherein X ₇ is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha.

In yet an even more highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 31-36 amino acids and comprising X6-X7-P-G-X10- N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, wherein X ₆ is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha.

In yet an even more highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 32-36 amino acids and comprising P-X6-X7-P-G- X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, wherein X ₆ is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D- Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha.

In yet an even more highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 33-36 amino acids and comprising X4-P-X6-X7-P- G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31- X32-R-X34-X35-X36, wherein X ₄ is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F} or Cha.

In the most preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, said analogue consisting of 34-36 amino acids and comprising, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E- X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X3 6, wherein X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha.

In another embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue is selected from the list consisting of: X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y- S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26- X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27 -I-N-X30-

X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30-X31-X32-R-X34-X35- X ₃ 6, X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, X7-P-G-X10-N-A- T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S- A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31- X32-R-X34-X35-X36, X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, N-A-T-P-E- X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X3 6, A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X3 6, X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, and R-Y-Y-S-A-L-R-X26-X27- I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi is selected as A, G, and Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xie is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R, or H; X27 is selected as Y, or Cha; Xso is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

In yet an embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y- S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26- X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27 -I-N-X30- X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30-X31-X32-R-X34-X35- X ₃₆ , X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, X7-P-G-X10-N-A- T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S- A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31- X32-R-X34-X35-X36, X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, N-A-T-P-E- X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X3 6, A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X3 6, X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, and A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A, or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

In another embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y- S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26- X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27 -I-N-X30-

X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30-X31-X32-R-X34-X35- X ₃ 6, X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, X7-P-G-X10-N-A- T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S- A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31- X32-R-X34-X35-X36, X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, N-A-T-P-E- X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X3 6, A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X3 6, and X17-A-R-Y-Y-S-A-L-R-X26-X27- I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xie is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution(s). In yet another embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S- A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27 - I-N-X30-X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30-X31-X32-R- X34-X35-X36, X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, X7-P-G- X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, P-G-X10-N-A-T-P-E-X16-X17-A- R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, N-A- T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26- X27-I-N-X30-X31-X32-R-X34-X35-X36, T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, P-E- X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X3 6, E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-

X31-X32-R-X34-X35-X36, and X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X3 6, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y, or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

In a preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S- A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27 - I-N-X30-X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30-X31-X32-R- X34-X35-X36, X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, X7-P-G- X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, P-G-X10-N-A-T-P-E-X16-X17-A- R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, N-A- T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26- X27-I-N-X30-X31-X32-R-X34-X35-X36, T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, P-E- X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X3 6, and E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xie is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D- Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

In another preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S- A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27 - I-N-X30-X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30-X31-X32-R- X34-X35-X36, X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, X7-P-G- X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, P-G-X10-N-A-T-P-E-X16-X17-A- R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, N-A- T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26- X27-I-N-X30-X31-X32-R-X34-X35-X36, T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, and P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X3 5-X36, wherein Xi is selected as A, G, or Aib; X ₄ is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

In yet another preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C- terminal fragment, wherein said analogue is selected from the list consisting of: X1-P-S-X4-P-X6-X7-P-G-X10- N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A- R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L- R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30- X31-X32-R-X34-X35-X36, X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35- X36, X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30 -X31-X32-R-X34-X35-X36, P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34- X35-X36, N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, A-T-P-E-X16-X17-A-R-Y-Y- S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, and T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xie is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

In a more preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue is selected from the list consisting of: X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S- A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27 - I-N-X30-X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30-X31-X32-R- X34-X35-X36, X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, X7-P-G- X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, P-G-X10-N-A-T-P-E-X16-X17-A- R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36, X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, N-A- T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, and A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

In yet a more preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C- terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G-X10- N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A- R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L- R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30- X31-X32-R-X34-X35-X36, X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35- X36, X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30 -X31-X32-R-X34-X35-X36, P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34- X35-X36, and N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xie is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s). In yet a more preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C- terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G-X10- N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A- R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L- R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30- X31-X32-R-X34-X35-X36, X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35- X36, X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30 -X31-X32-R-X34-X35-X36, P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, and X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R- X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

In yet a more preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C- terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G-X10- N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A- R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L- R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30- X31-X32-R-X34-X35-X36, X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35- X36, X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30 -X31-X32-R-X34-X35-X36, P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, and G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A- L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xie is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A, or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeQ, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution(s).

In an even more preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C- terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G-X10- N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A- R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L- R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30- X31-X32-R-X34-X35-X36, X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35- X ₃₆ , X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30 -X31-X32-R-X34-X35-X36, and P-G-X10-N-A- T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

In yet an even more preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G- X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T- P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X3 5-X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A- L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N- X30-X31-X32-R-X34-X35-X36, X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34- X35-X36, and X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30 -X31-X32-R-X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xie is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

In yet an even more preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G- X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T- P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X3 5-X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A- L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N- X30-X31-X32-R-X34-X35-X36, and X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R- X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xie is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

In yet an even more preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue is selected from the list consisting of: X1-P-S-X4-P-X6-X7-P-G- X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X3 2-R-X34-X35-X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T- P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X3 5-X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A- L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, and P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30-X31-X32-R-X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q,

D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-T rp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or is a derivative thereof having 1-2 amino acid substitution (s).

In a highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S- A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, and X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26- X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xie is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution(s).

In yet a highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C- terminal fragment, wherein said analogue is selected from the list consisting of X1-P-S-X4-P-X6-X7-P-G-X10- N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36, P-S-X4-P-X6-X7-P-G-X10-N-A-T-P- E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35- X36, and S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16- X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D,

E, or K; Xie is selected as E, Q, D, or N; X17 is selected as L, Nle, or M ; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s). In yet a highly preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C- terminal fragment, wherein said analogue is selected from the list consisting of: P-S-X4-P-X6-X7-P-G-X10-N- A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X3 4-X35-X36, and S-X4-P-X6-X7-P-G-X10-N-A-T-P-E- X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X3 6, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

In the most preferred embodiment, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue is selected as S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26-X27-I-N-X30-X31-X32-R-X34-X35-X36, wherein Xi is selected as A, G, or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xie is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution(s).

Any of the embodiments described above for Z1 may be combined with any of the embodiments described above for Z2 to obtain a hybrid polypeptide for formula Z1-Z2. Thus, in the present context it should be understood that any length of Z1 (i.e. from 8 up to and including 18 amino acids) as disclosed herein may be covalently linked with any length of Z2 (i.e. from 18 up to an including 36 amino acids) disclosed herein. By "covalently linked", it should be understood that the C-terminal of Z1 is connected to the N-terminal of Z2 through an amide bond to obtain a polypeptide of formula Z1-Z2.

Thus, in an embodiment wherein Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue consists of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs), Z2 may comprise an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 18 amino acids (i.e. R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36) up to and including 36 amino acids (i.e. X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26-X27-I-N-X30-X31-X32- R-X34-X35-X36).

In another embodiment, wherein Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue consists of 9 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-Xg), Z2 may comprise an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 18 amino acids (i.e. R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36) up to and including 36 amino acids (i.e. X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26-X27-I-N-X30- X31-X32-R-X34-X35-X36).

In another embodiment, wherein Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue consists of 10 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9-Xio), Z2 may comprise an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 18 amino acids (i.e. R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36) up to and including 36 amino acids (i.e. X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26-X27-I- N-X30-X31-X32-R-X34-X35-X36).

In another embodiment, wherein Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue consists of 11 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn), Z2 may comprise an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 18 amino acids (i.e. R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36) up to and including 36 amino acids (i.e. X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26-X27-I- N-X30-X31-X32-R-X34-X35-X36).

In another embodiment, wherein Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue consists of 12 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2), Z2 may comprise an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 18 amino acids (i.e. R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36) up to and including 36 amino acids (i.e. X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26- X27-I-N-X30-X31-X32-R-X34-X35-X36).

In another embodiment, wherein Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue consists of 13 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3), Z2 may comprise an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 18 amino acids (i.e. R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36) up to and including 36 amino acids (i.e. X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26- X27-I-N-X30-X31-X32-R-X34-X35-X36).

In another embodiment, wherein Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue consists of 14 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn- X12-X13-X14), Z2 may comprise an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 18 amino acids (i.e. R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36) up to and including 36 amino acids (i.e. X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A- L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36). 1

In another embodiment, wherein Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue consists of 15 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn- X12-X13-X14-R), Z2 may comprise an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 18 amino acids (i.e. R-Y-Y-S-A-L-R.-X26-X27-I-N-X30-X31-X32-R.-X34- X35-X36) up to and including 36 amino acids (i.e. X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A- L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36).

In another embodiment, wherein Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue consists of 16 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K), Z2 may comprise an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 18 amino acids (i.e. R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34- X35-X36) up to and including 36 amino acids (i.e. X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A- L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36).

In another embodiment, wherein Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue consists of 17 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E), Z2 may comprise an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 18 amino acids (i.e. R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36) up to and including 36 amino acids (i.e. X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y- S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36).

In another embodiment, wherein Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue consists of 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E-S), Z2 may comprise an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 18 amino acids (i.e. R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36) up to and including 36 amino acids (i.e. X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y- S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36).

Likewise, an embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 18 amino acids (i.e. R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R- X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs) up to and including 18 amino acids (i.e. Xi-X ₂ -[Dpr*]-X -L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi -R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 19 amino acids (i.e. A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32- R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 20 amino acids (i.e. X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31- X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 21 amino acids (i.e. X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30- X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 22 amino acids (i.e. E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30- X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 23 amino acids (i.e. P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N- X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 24 amino acids (i.e. T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27-I- N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs- X9-X10-X11-X12-X13-X14-R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 25 amino acids (i.e. A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R-X26-X27- I-N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E-S). In another embodiment, wherein Z2 consists of 26 amino acids (i.e. N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26-X27-I-N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L- S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of U amino acids (i.e. X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L-R- X26-X27-I-N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L- S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 28 amino acids (i.e. G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L- R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L- S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 29 amino acids (i.e. P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S-A-L- R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L- S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3-Xi4-R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 30 amino acids (i.e. X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y-S- A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. X1-X2- [Dpr*]-X4-L-S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3- Xw-R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 31 amino acids (i.e. X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y-Y- S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. X1-X2- [Dpr*]-X4-L-S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-X8-X9-Xio-Xn-Xi2-Xi3- Xw-R-K-E-S). In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 32 amino acids (i.e. P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A-R-Y- Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. X1-X2- including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9-Xio-Xn-Xi2-Xi3-

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 33 amino acids (i.e. X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17-A- R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N-terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. X1-X2- including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9-Xio-Xn-Xi2-Xi3-

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 34 amino acids (i.e. S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N- terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9-Xio-Xn-Xi2-

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 35 amino acids (i.e. P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16-X17- A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N- terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9-Xio-Xn-Xi2- X13-X14-R-K-E-S).

In another embodiment, wherein Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 36 amino acids (i.e. X1-P-S-X4-P-X6-X7-P-G-X10-N-A-T-P-E-X16- X17-A-R-Y-Y-S-A-L-R-X26-X27-I-N-X30-X31-X32-R-X34-X35-X36), Z1 may comprise an analogue of a hGhrelin N- terminal fragment, wherein said analogue can be an amino acid sequence consisting of 8 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs) up to and including 18 amino acids (i.e. Xi-X2-[Dpr*]-X4-L-S-P-Xs-X9-Xio-Xn-Xi2- X13-X14-R-K-E-S).

Any of the embodiments described above for Z1 may be combined with any of the embodiments described above for Z2 to obtain a hybrid polypeptide for formula Z1-Z2. Thus, the hybrid peptides of general formula Z1-Z2 may have a sequence length of 24 amino acids (i.e. 8 from Z1 + 18 from Z2) and up to and including 54 amino acids (i.e. 18 from Z1 + 36 from Z2). Most preferably, the hybrid polypeptides of Formula Z1-Z2 has an amino acid sequence length of 26-51 amino acid residues.

In an embodiment, Z1 comprises an analogue of a hGhrelin N-terminal fragment, wherein said analogue consists of 8-18 amino acids, preferably 9-18 amino acids, more preferably 9-17 amino acids, even more preferably 9-16 amino acids, most preferably 15 amino acids. Preferably, Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 18-36 amino acids, such as 19-36 amino acids, preferably 20-36 amino acids, such as 21-36 amino acids, more preferably 22- 36 amino acids, such as 23-36 amino acids, even more preferably 24-36 amino acids, such as 25-36 amino acids. It is highly preferred that Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 26-36 amino acids, such as 27-36 amino acids. It is more highly preferred that Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 28-36 amino acids, such as 29-36 amino acids. It is even more highly preferred that Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 30-36 amino acids, such as 31-36 amino acids. It is yet even more highly preferred that Z2 comprises an analogue of hNPY or an analogue of a hNPY C-terminal fragment, wherein said analogue consists of 32-36 amino acids, such as 33-36 amino acids, most preferably 34-36 amino acids, such as 34-35 amino acids, such as 34 amino acids. In should be appreciated that any of the ranges for the amino acid lengths of Z1 and Z2 may be combined to obtain a hybrid polypeptide of formula Zl- Z2.

In any of the above-mentioned embodiments described for Z2, the amino acids in Z2 is selected as follows: Xi is selected as G, A or Aib; X4 is selected as K, Q, E, or R; Xe is selected as V, T, K, or Q; X7 is selected as Y, K, or Q; X10 is selected as D, E, or K; Xi6 is selected as E, Q, D, or N; X17 is selected as L, Nle, or M; X26 is selected as R or H; X27 is selected as Y or Cha; X30 is selected as W, L, or Nle; X31 is selected as A or Aib; X32 is selected as Aib or T; X34 is selected as Q, NMeAla, NMeGIn, Aib, D-Trp, D-GIn, or D-Ala; X35 is selected as R or i R; X36 is selected as Y, Phe(4F), or Cha; or Z2 is derivative of any such sequence having 1-2 amino acid substitution (s).

Preferably, Xi in Z2 is selected as G (1), A (2), or Aib (3), wherein (1) is the most preferred and (3) the least preferred amino acid.

Preferably, X4 in Z2 is selected as K (1), Q (2), E (3), or R (4), wherein (1) is the most preferred and (4) the least preferred amino acid. Preferably, Xe in Z2 is selected as V (1), T (2), K (3), or Q (4), wherein (1) is the most preferred and (4) the least preferred amino acid.

Preferably, X? in Z2 is selected as Y (1), K (2), or Q (3), wherein (1) is the most preferred and (3) the least preferred amino acid.

Preferably, Xio in Z2 is selected as D (1), E (2), or K (3), wherein (1) is the most preferred and (3) the least preferred amino acid.

Preferably, Xi6 in Z2 is selected as E (1), Q (2), D (3), or N (3), wherein (1) is the most preferred and (3) the least preferred amino acid.

Preferably, X17 in Z2 is selected as L (1), Nle (2), or M (3), wherein (1) is the most preferred and (3) the least preferred amino acid.

Preferably, X26 in Z2 is selected as R (1), or H (2), wherein (1) is the most preferred and (2) the least preferred amino acid.

Preferably, X27 in Z2 is selected as Y (1), or Cha (2), wherein (1) is the most preferred and (2) the least preferred amino acid.

Preferably, X30 in Z2 is selected as W (1), L (2), or Nle (3), wherein (1) is the most preferred and (3) the least preferred amino acid.

Preferably, X31 in Z2 is selected as A (1), or Aib (2), wherein (1) is the most preferred and (2) the least preferred amino acid.

Preferably, X32 in Z2 is selected as Aib (1) or T (2), wherein (1) is the most preferred and (2) the least preferred amino acid.

Preferably, X34 in Z2 is selected as Q (1), NMeAla (2), NMeGIn (3), Aib (4), D-Trp (5), D-GIn (6), or D-Ala (7), wherein (1) is the most preferred and (7) the least preferred amino acid.

Preferably, X35 in Z2 is selected as R (1), or i R (2), wherein (1) is the most preferred and (2) the least preferred amino acid.

Preferably, Xse in Z2 is selected as Y (1), Phe(4F) (2), or Cha (3), wherein (1) is the most preferred and (3) the least preferred amino acid.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 shows percent body weight of the mice at day 7 in three treatment groups in comparison with the mice in the vehicle group (placebo group). The weight at day 0 is set as 100 percent. The three treatment groups were administered SEQ ID NO: 74 in 300 nmol/kg, 1000 nmol/kg and 3000 nmol/kg BID, respectively. As shown, the mice in the vehicle group had lost body weight at day 7, whereas the treatment groups showed a dose dependent increase in body weight at day 7.

EXPERIMENTAL

Peptide synthesis

Peptides were synthesized using standard Fmoc (fluorenylmethyloxycarbonyl) chemistry using Rink Amide HMBA Resin (0.30 mmol, 1.00 eq., loading 0.28 mmol/g). Fmoc removal was performed using 20% piperidine in dimethylformamide (DMF) (10 mL) and agitated with nitrogen for 15 min. The resin was washed with dimethylformamide (DMF) five times (10 mL) and filtered. The consecutive amino acid couplings were performed using a solution of 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU) (2.85 eq.), N,N-diisopropylethylamine (DIPEA) (6 eq) and Fmoc-protected amino acids (3 eq.) in dimethylformamide (DMF) (5 mL) and agitated with nitrogen bubbling for 30 min at 20°C. The resin was then washed five times with dimethylformamide (DMF) (10 mL). The Fmoc-protected amino acids building blocks used were the standard recommended: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Cys(tBu)-OH, Fmoc-Met-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc- Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc- Lys(Dde)-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Val-OH, Fmoc-Dpr(octanoyl)-OH, Fmoc-Cha-OH, Fmoc-NMeAla-OH, Fmoc- NMeGln(Trt)-OH, Fmoc-Phe(4F)-OH, Fmoc-Tle-OH, Fmoc-Aib-OH, Fmoc-lNal-OH, Fmoc-Nle-OH, Fmoc-D- Trp(Boc)-OH, Fmoc-D-Gln(Trt)-OH, Fmoc-D-Ala-OH, Boc-Pro-OH, Boc-NMePro-OH, Boc-Gly-OH, Boc- NMeGly-OH, Boc-Pip-OH, Boc-Nip-OH, Fmoc-i Arg(Pbf)-Tyr(tBu)-OH, Fmoc-OEG-OH, Fmoc-Glu-OtBu, Eicosanedioic acid mono-tert-butyl ester, and Octadecanedioic acid mono-tert-butyl ester. If nothing else is specified, the natural L-form of the amino acids was used. Fmoc removal and coupling steps were repeated until the desired peptide sequence was achieved. The resultant linear peptide was used directly in the next step. To remove the Dde protecting group, 3% N2H4‘H2O in DMF was added and left to react for 30 min - drain and repeat the deprotection. Elongation at the side-chain of the deprotected Lys as described for the standard couplings and Fmoc-deprotection but using 2-(lH-7-Azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronoium hexafluorphosphate (HATU) as coupling reagent instead of HBTU. Peptide cleavage and purification

The resin was washed with methanol (20 mL x 5) and dried under vacuum to get peptide resin. Subsequently, the peptidyl resin was then treated with the cleavage cocktail (92.5% TFA (trifluoroacetic acid)/ 2.5% triisopropyl silane (TIPS) I 2.5% 3-mercaptopropionic acid (Mpr) I 2.5% H2O) (15 mL) for 150 min and the peptide TFA mixture was collected. The peptide was precipitated with cold isopropyl ether and centrifuged (2 min at 3000 rpm). Wash the peptide precipitation with isopropyl ether for two more times. Dry the crude peptide over vacuum for 2 hours. The peptide was re-dissolved in an acetonitrile/water mixture and purified by preparative HPLC and the target peptide fractions was freeze dried to give a white solid.

Preparative HPLC purification method:

System: Gilson GX-281

Column: Gemini, 5 pm, C18, 110 A followed by a Luna, C18, 10 pm, 100 A.

Gradient: 21-41% 0-50 min.

Flow rate: 20 mL/min

Diode array: 214/254 nm

Column temperature: 30°C

Solvent A: 0.075% TFA in water

Solvent B: Acetonitrile

HPLC QC method:

System: Agilent Infinity II 1260 HPLC series

Column: Gemini C18, llOA, 5 pm, 150 x 4.6 mm

Gradient: Gradient run-time 20 min; 0.00-20.00 min 15-45% B. Column cleaning and equilibration; 20.00-20.10 min 45-95% B, 20.10-23.00 min 95% B, 23.00- 23.10 min 95-15% B, 23.10-28.00 min 15% B

Flow rate: 1.0 mL/min

Diode array: 220/254 nm

Column temperature: 30°C

Solvent A: 0.1% TFA in water

Solvent B: 0.075% TFA in acetonitrile

LC-MS method for final products:

System: Agilent Infinity II 1260 HPLC series

Column: Xbridge C18, 130A, 3.5 pm, 2.1 x 30 mm

Detector: Agilent LCMS (G6125C), single quadrupole TIC scan

Scanning range: m/z min 100, m/z max. 2000, positive mode Gradient: Gradient run-time 1 min; 0.00-1.00 min 10-80% B. Column cleaning and equilibration; 1.00-1.01 min 80-95% B, 1.01-1.60 min 95% B, 1.60-1.61 min 95-10% B, 1.61-2.00 min 10% B

Flow rate: 1.2 mL/min Diode array: 220/254 nm

Column temperature: Room temperature

Solvent A: 0.1% TFA in water

Solvent B: 0.075% TFA in acetonitrile

In vitro assays

The in vitro functional measurements were all performed by EuroScreen Fast, a CRO unit of Epics Therapeutics S.A., in Gosselies, Belgium. The peptides were tested towards hGHSR using IPOne HTRF functional assays. The hGHSR receptor accession numbers, cellular background, and reference compounds are GHSR NP_940799.1, CHO-Kl-mt aequorin, and human Ghrelin, respectively. And the peptides were tested towards hNPY5R using cAMP HTRF assay. The hNPY5R receptor accession numbers, cellular background, and reference compounds are NPY5R AAC50623.1, CHO-K1, and human NPY, respectively. On each day of experimentation, reference compounds were tested at several concentrations in duplicate (n=2-3) to obtain a dose-response curve and an estimated ECso value. Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session. For replicate determinations, the maximum variability tolerated in the test was of +/- 20% around the average of the replicates. Dose-response data from test compounds were analysed with XLfit (IDBS) software using nonlinear regression applied to a sigmoidal dose-response model and the following equation:

XL Fit Model 203: 4 Parameter Logistic Model

A: Bottom B: TOP C: LogEC50 20 D: Hill fit= (A+((B-A)/(l+(((10 C)/x) D)))) inv= ((10 ^A C)/((((B-A)/(y-A))-l) ^A (l/D))) res = (y-fit)

In vivo experiment

The study was performed by CRO APIGENEX s.r.o. in vivo pharmacology department, Czech Republic. 32 C57BL/6J mice, males, 10 weeks old at the arrival (Charles River, Germany). The mice were kept under controlled conditions with constant temperature (22 ± 2 °C), relative humidity 45-65 %, fixed dark:light cycle (light off at 7 pm, light on at 7 am) and supplied with standard environmental enrichment (plastic houses, nesting material, aspen blocks). The animals were housed singly and acclimatized for 6 days before the start of experiment. The bedding (Jeluxyl-Sawi, Germany) was exchanged twice weekly. The mice were supplied with normal chow (Ssniff R/M-H, Germany) ad libitum throughout the study. The animals had free access to UV light-treated drinking water. The water was exchanged twice weekly.

The compounds were dissolved in 5 mM acetate buffer + 5% w/v mannitol, pH=4. The test items were formulated on day -1 and divided into 7 daily aliquots. The aliquots were stored at -20 °C, thawed at room temperature 60 min prior to morning dosing and kept in refrigerator for the afternoon dosing. The vehicle and the compounds were dosed subcutaneously in volume of 10 ml/kg in the scruff of the neck on days 0- 6 at 7 am and at 6 pm. Every day the clinical observations of all mice were recorded. The body weight was determined on days 0- 7 at 6:20 am using calibrated scales Mettler-Toledo PB3002-S. The individual food intake was determined on days 1-7 at 7 am using calibrated scales Mettler-Toledo PB3002-S. The food was equilibrated to animal room humidity for 4 days. At each time point, pre-weighed diet (approximately 25 g per animal) was presented. The food intake was calculated as a difference between the diet amount supplied and the residual amount.

REFERENCES 1. Chiara Cabrele, Michael Langer, Reto Bader, Heike A. Wieland, Henri N. Doods, Oliver Zerbe, and

Annette G. Beck-Sickinger. J. Biol. Chem, 2000, 275 (46), pp. 36043-36048.