NRF2-DERIVED POLYPEPTIDES AND PROTEIN-LIKE POLYMER

CONJUGATES THEREOF

CROSS-REFERENCE

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/413,524 filed October 5, 2022, which is incorporated by reference in its entirety herein.

FIELD OF THE DISCLOSURE

[0002] The disclosure generally relates to polypeptides including a peptide derived from Nrf2 and a charge-modulating peptide. The disclosure additionally relates to conjugates where the polypeptide is attached to polymers that enhance the biological activity of the polypeptide.

BACKGROUND

[0003] Inefficiencies in cellular uptake and degradation by extracellular proteases are two limitations that have hampered the clinical adoption of many protein/peptide-based therapeutics. As a result of these limitations, many peptide therapeutics are administered by injection directly to the site of action to improve their bioavailability.

[0004] The Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and Kelch-like ECH- Associating protein 1 (Keapl) protein-protein interaction is a key molecular event that is important in a number of diseases such as cancer, autoimmune diseases, inflammatory disease, and neurodegenerative diseases including Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease. Disrupting the protein-protein interaction between Keapl and Nrf2 has been an actively investigated therapeutic strategy for enhancing antioxidant and antiinflammatory responses in a number of diseases. For example, Colarusso et al. (Bioorganic Med. Chem., 28; 1-12 (2020)) describe linear and cyclic peptides based on the Nrf2 ETGE motif (SEQ ID NO: 613) that inhibit the Keapl/Nrf2 protein-protein interaction. However, the peptide inhibitors described by Colarusso et al. were physiologically inactive as they lacked the ability to pass through the cell membrane.

[0005] Several approaches have been employed to address the issue of digestion of therapeutic peptides by proteases including: modification of the amino acid sequence, and conjugation to high molecular weight structures, such as polymers or nanomaterials. These approaches are associated with their own drawbacks such as the requirement for additional synthesis and purification steps, and the need to be released form high molecular weight carriers.

[0006] Thus, there remains a need for improved delivery strategies for therapeutic peptides, such as those targeting the Keapl/Nrf2 protein-protein interaction.

BRIEF SUMMARY OF THE DISCLOSURE

[0007] The present disclosure is directed to compositions and methods of using polypeptides and polymers for reducing the risk of, preventing, and treating oxidative stress and inflammation.

[0008] In certain aspects, the present disclosure provides a polypeptide including a peptide having a sequence at least 93% identical, or 100% identical, to SEQ ID NO: 1 (ILWRQDIDLGVSREV), and a charge-modulating peptide, where the polypeptide is 17 to 22 amino acids long.

[0009] In some aspects, the present disclosure provides a polymer including a first polymer segment having at least two first repeating units, where each of the first repeating units includes a first polymer backbone group directly or indirectly covalently linked to a first polymer side chain group including a peptide having a sequence at least 93% identical, or 100% identical to SEQ ID NO: 1 (ILWRQDIDLGVSREV). In some aspects, the first polymer side chain group further comprises a charge-modulating peptide

[0010] In some aspects the charge-modulating peptide of the polypeptide or first polymer side chain group is 2 to 7 amino acid residues long. In some aspects the charge-modulating peptide is a glycine-serine peptide, a cationic residue peptide, or a combination thereof. In some aspects the cationic residue peptide comprises lysine, arginine, histidine, or a combination thereof. In some aspects the polypeptide has a net positive charge. In some aspects, the polypeptide has a sequence 100% identical to any one of SEQ ID NOs: 3 to 574. In some aspects, the peptide includes a sequence 100% identical to any one of SEQ ID NOs: 575-592.

[0011] In some aspects the polymer is a homopolymer, copolymer, or a brush polymer. In some aspects the brush polymer has a brush density greater than or equal to 50%, greater than or equal to 70%, or greater than or equal to 90%.

[0012] In some aspects, the first polymer segment includes at least five repeating units. In some aspects the first polymer segment includes 5 to 30 first repeating units.

[0013] In some aspects, the polymer has a degree of polymerization of 2 to 1000. In some aspects, the polymer has a poly dispersity index less than 1.75. [0014] In some aspects, the first polymer side chain group is linked to the first polymer backbone group via an enzymatically degradable linker or triggerable linker. In some aspects, the enzymatically degradable linker or triggerable linker is a matrix metalloproteinase (MMP) cleavage sequence, cathepsin B cleavage sequence, ester bond, reductive sensitive bond, disulfide bond, pH sensitive bond, imine bond, or combination thereof.

[0015] In some aspects, the polymer further includes a tag for imaging and/or analysis, one or more additional peptides and/or proteins, a non-ionic polymer, or a combination thereof.

[0016] In some aspects, polymers of the present disclosure have the formula: Q ^x -T-Q ² (Formula I); Q ¹ -T-[S] _h -Q ² (Formula II); (^-[SJn-T-Q ² (Formula III); Q ¹ -[S] _i -T-[S] _h -Q ² (Formula IV); Q ¹ -[S]i-T-[S]h-T-Q ² (Formula V); Q ¹ -T-[S]i-T-[S]h-Q ² (Formula VI); or Q ^x -T- [S]i-T-[S]h-T-Q ² (Formula VII), where each T is independently the first polymer segment, each S is independently an additional polymer segment, Q ¹ is a first backbone terminating group and Q ² is a second backbone terminating group, h is zero or an integer selected over the range of 1 to 1000, and i is zero or an integer selected over the range of 1 to 1000. In some aspects, each -T- is independently where each Y ¹ is independently the first repeating unit of the first polymer segment, and each m is independently zero or an integer selected over the range of 1 to 1000, provided that at least one m is an integer selected over the range of 1 to 1000. (

[0017] In some aspects, polymers of the present disclosure have the formula: where each Z ¹ is independently a first polymer backbone group and each Z ² is independently a second polymer backbone group, each S is independently a repeating unit different than the first repeating unit, Q ¹ is a first backbone termination group and Q ² is a second backbone termination group, each L ¹ is independently a first linking group and each L ² is independently a second linking group, each P ¹ is the peptide and each P ² is a polymer side chain different than the peptide, each m is independently an integer selected over the range of 2 to 1000, each n is independently zero or an integer selected over the range of 1 to 1000, and each h is independently zero or an integer selected over the range of 1 to 1000. In some aspects, each of the first polymer backbone group and/or the second polymer backbone group is a substituted or unsubstituted polymerized norbornene, olefin, cyclic olefin, norbornene anhydride, cyclooctene, cyclopentadiene, styrene, acrylamide, or acrylate. In some aspects, each polymer backbone group of the polymer is a polymerized norbornene dicarboxyimide monomer.

[0019] In some aspects, each of Z ¹ and Z ² is independently a substituted or unsubstituted polymerized norbomene, oxanorbornene, olefin, cyclic olefin, cyclooctene, or cyclopentadiene.

[0020] In some aspects, each Z ¹ connected to L ¹ , P ¹ , or a combination thereof is independently characterized by the formula (Formula VIII) or (Formula IX): (Formula IX), and where each Z ² connected to L ² , and P ² or a combination thereof can independently be characterized by the formula (Formula X) or (Formula XI): p ² (Formula X) or ^p2 (Formula XI).

[0021] In some aspects, each of Q ¹ and Q ² can independently be selected from a hydrogen, C1-C30 alkyl, C3-C30 cycloalkyl, C5-C30 aryl, C5- C30 heteroaryl, C1-C30 acyl, Ci- C30 hydroxyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, Cs-Csoalkylaryl, — CO2R ³ , — CONR ⁴ R ⁵ , —COR ⁶ , — SOR ⁷ , — OSR ⁸ , — SO2R ⁹ , —OR ¹⁰ , — SR ¹¹ , — NR ¹² R ¹³ , — NR ¹⁴ COR ¹⁵ , C1-C30 alkyl halide, phosphonate, phosphonic acid, silane, siloxane, silsesquioxane, C2-C30 halocarbon chain, C2-C30 perfluorocarbon, C2-C30 polyethylene glycol, a metal, or a metal complex, where each of R ³ -R ¹⁵ is independently H, C5-C10 aryl or Ci- C10 alkyl.

[0022] In some aspects, each of L ¹ and L ² is independently selected from a single bond, an oxygen, and groups having an alkyl group, an alkenylene group, an arylene group, an alkoxy group, an acyl group, a triazole group, a diazole group, a pyrazole group, and combinations thereof. In some aspects, each of L ¹ and L ² is independently selected from a single bond, — O — , C1-C10 alkyl, C2- C10 alkenylene, C3- C10 arylene, Ci- C10 alkoxy, Ci- C10 acyl and combinations thereof.

[0023] In some aspects, a polymer of the present disclosure is stable against enzymatic digestion. In some aspects, a polymer of the present disclosure is stable against enzymatic digestion by a metalloproteinase such as a matrix metalloproteinase, or thermolysin.

[0024] In some aspects, the present disclosure provides a pharmaceutical composition including a peptide or polymer described herein and a pharmaceutically acceptable excipient.

[0025] In some aspects, the present disclosure provides a method of treating a condition including administering to a subject an effective amount of a peptide, polymer, or pharmaceutical composition described herein. In some aspects, administration is intravenous, subcutaneous, intramuscular, topical, oral, or a combination thereof. In some aspects, the condition is associated with an inflammatory state, increased oxidative stress, autoimmune pathophysiology, chemo-preventive measures, neurodegeneration, or a combination thereof. In some aspects, the condition is an autoimmune disease such as multiple sclerosis, systemic lupus erythematous, Sjogren syndrome, rheumatoid arthritis, vitiligo, or psoriasis. In some aspects, the condition is a respiratory disease such as COPD, emphysema, potential treatment for smokers, idiopathic pulmonary fibrosis, chronic sarcoidosis, or hypersensitivity pneumonitis. In some aspects the condition is a gastrointestinal disease such as ulcerative colitis, ulcers, prevent acetaminophen toxicity, non-alcoholic steatohepatitis, primary biliary cholangitis, cirrhosis, type 2 diabetes, or diabetic nephropathy. In some aspects, the condition is a cardiovascular disease such as cardiac ischemia-reperfusion injury, heart failure, or atherosclerosis. In some aspects, the condition is a neurodegenerative disease such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, Friedreich ataxia, or frontotemporal lobar degeneration.

[0026] In some aspects, the present disclosure provides a method for interrupting the protein-protein interaction between Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and Kelch-like ECH-Associating protein 1 (Keapl).

[0027] In some aspects, the present disclosure provides a method of treating a condition in a subject including administering to a subject an effective amount of a polymer including a first polymer segment comprising at least 5 first repeating units, where each of the first repeating units of the first polymer segment comprises a first polymer backbone group directly or indirectly covalently linked to a first polymer side chain group including a peptide; where the peptide has a sequence having at least 93% sequence identity to SEQ ID NO: 1 (ILWRQDIDLGVSREV). In some aspects, the present disclosure provides a method of treating a condition in a subject including: administering to a subject an effective amount of a polymer including a first polymer segment comprising at least 5 first repeating units, where each of the first repeating units of the first polymer segment includes a first polymer backbone group directly or indirectly covalently linked to a first polymer side chain group including a peptide, where the peptide has a sequence having 100% sequence identity to any one of SEQ ID NOs:575-592. In some aspects, the condition is associated with an inflammatory state, increased oxidative stress, autoimmune pathophysiology, chemo- preventative measures, neurodegeneration, or a combination thereof. DETAILED DESCRIPTION

[0028] The present disclosure provides compositions of polypeptides and protein-like polymers (PLPs) for reducing the risk of, preventing, and treating oxidative stress and inflammation. The present disclosure also provides methods for using polypeptides and PLPs for reducing the risk of, preventing, and treating oxidative stress and inflammation in various diseases and conditions.

[0029] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0030] The following abbreviations are used herein: “Keapl” refers to Kelch-like ECH associated protein 1; “Nrf2” refers to Nuclear factor-erythroid factor 2-related factor 2; “BBB” refers to blood-brain-barrier; “CNS” refers to central nervous system; “SPPS” refers to solid phase peptide synthesis; “ROMP” refers to ring-opening metathesis polymerization; “RAFT” refers to reversible addition fragmentation chain transfer polymerization; “DMF” refers to dimethylformamide; “TFA” refers to tri fluoroacetic acid; “TIPS” refers to triisopropyl silane; “DTT” refers to dithiothreitol; “LJ” refers to Lennard- Jones; “RP-HPLC” refers to reverse-phase high performance liquid chromatography; “ESI-MS” refers to electrospray ionization mass spectrometry; “NMR” refers to nuclear magnetic resonance spectrometry; “MALDI-MS” refers to matrix-assisted laser desorption/ionization mass spectrometry; “SEC-MALS” refers to size-exclusion chromatography coupled with multiangle light scattering; “GPC” refers to gel permeation chromatography; “SDS- PAGE” refers to sodium dodecyl sulfate-polyacrylamide gel electrophoresis; “CD” refers to circular dichroism; “SAXS” refers to Small-angle X-ray scattering; “ARE” refers to antioxidant response element; “BSA” refers to bovine serum albumin; “tBHQ” refers to tert- Butylhydroquinone; “PLP” refers to protein-like polymer; “ “MW” refers to molecular weight; and “DP” refers to degree of polymerization.

[0031] As used herein “PDF’ refers to poly dispersity index. The PDI is a measure of broadness of molecular weight distribution. The PDI of a polymer is calculated as the ratio of weight average (z.e., molecular weight measurements depending on the contributions of a molecule’s size as measured by light scattering or ultracentrifugation) by number average molecular weight (i.e. the total weight of the molecules present divided by the total number of molecules). For example, monodisperse polymers having all chains of the same length have a PDI value of 1. [0032] In some embodiments, a peptide, a polymer, or a composition e.g., formulation), as presently disclosed, is isolated or purified. In some embodiments, an isolated or purified peptide, polymer, or composition (e.g., formulation) is at least partially isolated or purified as would be understood in the art. In some embodiments, the peptide, polymer, or composition (e.g., formulation) has a chemical purity of at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure. Also described herein are isolated and purified compositions of any of the brush polymers (e.g., brush homopolymers and peptide brush copolymers) including the brush block polymers or brush random polymers having one or more side chains comprising the peptide analogues, derivative, variants or fragments.

[0033] As used herein, the term “polymer” refers to a molecule composed of two or more repeating structural units connected by covalent chemical bonds. In some embodiments, polymers are composed of 2 to 2000 repeating structural units (e.g., 2 to 2000, 4 to 2000, 8 to 2000, 10 to 2000, 15 to 2000, 20 to 2000, 25 to 2000, 50 to 2000, 75 to 2000, 100 to 2000, 150 to 2000, 200 to 2000, 300 to 2000, 400 to 2000, 500 to 2000, 600 to 2000, 700 to 2000, 800 to 2000, 900 to 2000, 1000 to 2000, 1100 to 2000, 1200 to 2000, 1300 to 2000, 1400 to 2000, 1500 to 2000, 1600 to 2000, 1700 to 2000, 1800 to 2000, 1900 to 2000, 2 to 1500, 4 to 1500, 8 to 1500, 10 to 1500, 15 to 1500, 20 to 1500, 25 to 1500, 50 to 1500, 75 to 1500, 100 to 1500, 150 to 1500, 200 to 1500, 300 to 1500, 400 to 1500, 500 to 1500, 600 to 1500, 700 to 1500, 800 to 1500, 900 to 1500, 1000 to 1500, 1100 to 1500, 1200 to 1500, 1300 to 1500, 1400 to 1500, 2 to 1000, 4 to 1000, 8 to 1000, 10 to 1000, 15 to 1000, 20 to 1000, 25 to 1000, 50 to 1000, 75 to 1000, 100 to 1000, 150 to 1000, 200 to 1000, 300 to 1000, 400 to 1000, 500 to 1000, 600 to 1000, 700 to 1000, 800 to 1000, 900 to 1000, 2 to 500, 4 to 500, 8 to 500, 10 to 500, 15 to 500, 20 to 500, 25 to 500, 50 to 500, 75 to 500, 100 to 500, 150 to 500, 200 to 500, 300 to 500, 400 to 500, 2 to 100, 4 to 100, 8 to 100, 10 to 100, 15 to 100, 20 to 100, 25 to 100, 50 to 100, 75 to 100, 2 to 50, 4 to 50, 8 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 2 to 10, 4 to 10, or 8 to 10).

[0034] In some embodiments, polymers of the present disclosure have high molecular weights (e.g., 1 kDa to 100 kDa, 5 kDa to 100 kDa, 10 kDa to 100 kDa, 15 kDa to 100 kDa, 25 kDa to 100 kDa, 30 kDa to 100 kDa, 35 kDa to 100 kDa, 40 kDa to 100 kDa, 45 kDa to 100 kDa, 50 kDa to 100 kDa, 55 kDa to 100 kDa, 60 kDa to 100 kDa, 65 kDa to 100 kDa, 70 kDa to 100 kDa, 75 kDa to 100 kDa, 80 kDa to 100 kDa, 85 kDa to 100 kDa, 90 kDa to 100 kDa, 95 kDa to 100 kDa, 1 kDa to 90 kDa, 5 kDa to 90 kDa, 10 kDa to 90 kDa, 15 kDa to 90 kDa, 25 kDa to 90 kDa, 30 kDa to 90 kDa, 35 kDa to 90 kDa, 40 kDa to 90 kDa, 45 kDa to 90 kDa, 50 kDa to 90 kDa, 55 kDa to 90 kDa, 60 kDa to 90 kDa, 65 kDa to 90 kDa, 70 kDa to 90 kDa, 75 kDa to 90 kDa, 80 kDa to 90 kDa, 85 kDa to 90 kDa, 1 kDa to 80 kDa, 5 kDa to 80 kDa, 10 kDa to 80 kDa, 15 kDa to 80 kDa, 25 kDa to 80 kDa, 30 kDa to 80 kDa, 35 kDa to 80 kDa, 40 kDa to 80 kDa, 45 kDa to 80 kDa, 50 kDa to 80 kDa, 55 kDa to 80 kDa, 60 kDa to 80 kDa, 65 kDa to 80 kDa, 70 kDa to 80 kDa, 75 kDa to 80 kDa, 1 kDa to 70 kDa, 5 kDa to 70 kDa, 10 kDa to 70 kDa, 15 kDa to 70 kDa, 25 kDa to 70 kDa, 30 kDa to 70 kDa, 35 kDa to 70 kDa, 40 kDa to 70 kDa, 45 kDa to 70 kDa, 50 kDa to 70 kDa, 55 kDa to 70 kDa, 60 kDa to 70 kDa, 65 kDa to 70 kDa, 1 kDa to 60 kDa, 5 kDa to 60 kDa, 10 kDa to 60 kDa, 15 kDa to 60 kDa, 25 kDa to 60 kDa, 30 kDa to 60 kDa, 35 kDa to 60 kDa, 40 kDa to 60 kDa, 45 kDa to 60 kDa, 50 kDa to 60 kDa, 55 kDa to 60 kDa, 1 kDa to 50 kDa, 5 kDa to 50 kDa, 10 kDa to 50 kDa, 15 kDa to 50 kDa, 25 kDa to 50 kDa, 30 kDa to 50 kDa, 35 kDa to 50 kDa, 40 kDa to 50 kDa, 45 kDa to 50 kDa, 1 kDa to 40 kDa, 5 kDa to 40 kDa, 10 kDa to 40 kDa, 15 kDa to 40 kDa, 25 kDa to 40 kDa, 30 kDa to 40 kDa, 35 kDa to 40 kDa, 1 kDa to 30 kDa, 5 kDa to 30 kDa, 10 kDa to 30 kDa, 15 kDa to 30 kDa, 25 kDa to 30 kDa, 1 kDa to 20 kDa, 5 kDa to 20 kDa, 10 kDa to 20 kDa, 15 kDa to 20 kDa, 25 kDa to 20 kDa, 30 kDa to 20 kDa, 35 kDa to 20 kDa, 40 kDa to 20 kDa, 45 kDa to 20 kDa, 50 kDa to 20 kDa, 55 kDa to 20 kDa, 60 kDa to 20 kDa, 65 kDa to 20 kDa, 70 kDa to 20 kDa, 75 kDa to 20 kDa, 80 kDa to 20 kDa, 85 kDa to 20 kDa, 90 kDa to 20 kDa, 95 kDa to 20 kDa, 1 kDa to 10 kDa, or 5 kDa to 10 kDa).

[0035] In some embodiments, a polymer as disclosed herein is the polymerization product of one or more monomer precursors. In some embodiments, a polymer is a homopolymer composed essentially of a single repeating monomer subunit. In some embodiments, a polymer is a copolymer composed of repeating units of two or more different monomer subunits covalently linked together. In some embodiments, copolymers described herein include two or more monomer subunits (e.g. 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 12 to 20, 14 to 20, 16 to 20, 18 to 20, 2 to 15, 3 to 15, 4 to 15, 5 to 15, 6 to 15, 7 to 15, 8 to 15, 9 to 15, 10 to 15, 12 to 15, 14 to 15, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 2 to 5, 3 to 5, or 4 to 5). For example, in some embodiments, copolymers of the present disclosure are composed of 2, 3, 4, 5, 6, 7, 8, 9, or 10 different monomer subunits.

[0036] In some embodiments, copolymers of the present disclosure have random, block, brush, brush block, alternating, segmented, grafted, tapered, or other architecture. [0037] As used herein, the term “polymer segment” (e.g., first polymer segment, second polymer segment, etc.) refers to a section or portion of the polymer composed of a particular monomer or arrangement of monomers. In some embodiments, a polymer segment can be a homopolymer or a copolymer. In some embodiments, where a polymer segment is a copolymer, the copolymer can exist in any suitable arrangement of monomers (e.g., random, block, brush, brush block, alternating, segmented, grafted, tapered, statistical or other architecture). In some embodiments, the polymer segments are homopolymers, random copolymers, statistical copolymers or block copolymers. Any polymer (e.g., brush polymer) described herein can have a single polymer segment or multiple polymer segments. In some embodiments where the polymer has multiple polymer segments, the polymer segments can exist in any suitable arrangement (e.g., random, block, brush, brush block, alternating, segmented, grafted, tapered, statistical, or other architecture).

[0038] An “oligomer” refers to a molecule composed of repeating structural units connected by covalent chemical bonds often characterized by a number of repeating units less than that of a polymer (e.g., equal to or less than 3 repeating units) and a lower molecular weights (e.g., less 20 than or equal to 1,000 Da) than polymers. Oligomers may be the polymerization product of one or more monomer precursors.

[0039] The terms “peptide” or “oligopeptide” are used interchangeably herein and refer to a polymer of repeating structural units connected by a peptide bond. Typically, the repeating structural units of the peptide are amino acids including naturally occurring amino acids, non-naturally occurring amino acids, analogues of amino acids or any combination of these. The number of repeating structural units of a peptide, as understood in the art, are typically less than a “protein,” and thus the peptide often has a lower molecular weight than a protein.

[0040] As used herein, the term “block copolymer” refers to a type of copolymer composed of blocks or spatially segregated domains, wherein different domains include different polymerized monomers, for example, including at least two chemically distinguishable blocks. Block copolymers may further include one or more other structural domains, such as hydrophobic groups, hydrophilic groups, etc. In a block copolymer, adjacent blocks are constitutionally different, i.e., adjacent blocks comprise constitutional units derived from different species of monomer or from the same species of monomer but with a different composition or sequence distribution of constitutional units. Different blocks (or domains) of a block copolymer may reside on different ends or the interior of a polymer e.g., [A] [B]), or may be provided in a selected sequence (e.g., [A] [B] [A] [B]). The term “diblock copolymer” refers to a block copolymer having two different polymer blocks. The term “triblock copolymer” refers to a block copolymer having three different polymer blocks, including compositions in which two non-adjacent blocks are the same or similar. The term “pentablock” copolymer refers to a copolymer having five different polymer blocks including compositions in which two or more non-adjacent blocks are the same or similar.

[0041] “Random copolymers” are a type of copolymer composed of spatially randomized units, wherein at least two chemically distinguishable polymerized monomers are randomly distributed throughout the polymer.

[0042] A “polymer backbone group” refers to a group that is covalently linked to make up a backbone of a polymer, such as a block copolymer or a random copolymer. Polymer backbone groups may be linked to side chain groups, such as polymer side chain groups. In some embodiments, polymer backbone groups are derived from the polymerization of a monomer selected from a substituted or unsubstituted norbomene, olefin, cyclic olefin, norbomene anhydride, cyclooctene, cyclopentadiene, styrene, acrylamide, or acrylate. In some embodiments, polymer backbone groups are obtained from a ring opening metathesis polymerization (ROMP) reaction. In some embodiments, polymer backbones may terminate in a range of backbone terminating groups including hydrogen, Ci-Cio alkyl, C3-C10 cycloalkyl, Cs-Cio aryl, C5-C10 heteroaryl, Ci-Cio acyl, Ci-C 10 hydroxyl, Ci-C 10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C5-C10 alkylaryl, -CO2R ³⁰ , -CONR ³¹ R ³² , -COR ³³ ,-SOR ³⁴ , -OSR ³⁵ , - SO2R ³⁶ ,-OR ³⁷ , -SR ³⁸ , -NR ³⁹ R ⁴⁰ , -NR ⁴¹ COR ⁴² , C1-C10 alkyl halide, phosphonate, phosphonic acid, silane, siloxane, acrylamide, acrylate, or catechol; wherein each of R3o-R42 is independently hydrogen, C1-C10 alkyl or C5-C10 aryl.

[0043] A “polymer side chain group” refers to a group covalently linked (directly or indirectly) to a polymer backbone group that includes a polymer side chain. In some embodiments, the polymer side chain group imparts steric properties to the polymer. In some embodiments, a polymer side chain group is characterized by a plurality of repeating units having the same, or similar, chemical composition. In some embodiments, a polymer side chain group may be directly or indirectly linked to the polymer backbone groups. In some embodiments, polymer side chain groups provide steric bulk and/or interactions that result in an extended polymer backbone and/or a rigid polymer backbone. In some embodiments, polymer side chain groups include unsubstituted or substituted peptide groups. In some embodiments, polymer side chain groups include repeating units obtained via anionic polymerization, cationic polymerization, free radical polymerization, group transfer polymerization, or ring-opening polymerization. In some embodiments, a polymer side chain may terminate in a wide range of polymer side chain terminating groups including hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, Cs-Cio aryl, C5-C10 heteroaryl, Ci-Cio acyl, C1-C10 hydroxyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C5-C 10 alkylaryl, -CO2R ³⁰ , -CONR ³¹ R ³² , - COR ³³ ,-SOR ³⁴ , -OSR ³⁵ , -SO ₂ R ³⁶ ,-OR ³⁷ , -SR ³⁸ , -NR ³⁹ R ⁴⁰ , -NR ⁴¹ COR ⁴² , C1-C10 alkyl halide, phosphonate, phosphonic acid, silane, siloxane, acrylamide, acrylate, or catechol; wherein each of R ³⁰ -R ⁴² is independently hydrogen or C1-C5 alkyl.

[0044] As used herein, the term “degree of polymerization” refers to the average number of monomer units per polymer chain. For example, for certain polymers described herein, comprising Z ¹ , Z ² , and/or S monomer units, the degree of polymerization is represented by the sum total of Z ¹ , Z ² , and S monomer units. Since the degree of polymerization can vary from polymer to polymer, the degree of polymerization is generally represented by an average. Polymerization can be monitored by any one or more methods known to persons of skill in the art such as ¹ H NMR spectroscopy and size exclusion chromatography coupled with multiangle light scattering (SEC-MALS).

[0045] As used herein, the term “brush polymer” refers to a polymer comprising repeating units, each independently including a polymer backbone group covalently linked to at least one polymer side chain group. A brush polymer may be characterized by brush density which refers to the percentage of the repeating units having polymer side chain groups. In some embodiments, brush polymers have a brush density greater than or equal to 50% (e.g., greater than or equal to 55%, greater than or equal to 60%, greater than or equal to 65%, greater than or equal to 70%, greater than or equal to 75%, greater than or equal to 80%, greater than or equal to 85%, greater than or equal to 90%, or greater than or equal to 95%). In some embodiments, brush polymers have a density greater than or equal to 70%. In some embodiments, brush polymers have a density greater than or equal to 90%. In some embodiments, brush polymers have a density from 50% to 100%, 55% to 100%, 60% to 100%, 65% to 100%, 70% to 100%, 75% to 100%, 80% to 100%, 85% to 100%, 90% to 100%, 95% to 100%, 50% to 90%, 55% to 90%, 60% to 90%, 65% to 90%, 70% to 90%, 75% to 90%, 80% to 90%, 85% to 90%, 50% to 80%, 55% to 80%, 60% to 80%, 65% to 80%, 70% to 80%, 75% to 80%, 50% to 70%, 55% to 70%, 60% to 70%, 65% to 70%, 50% to 60%, or 55% to 60%. [0046] As used herein, the term “peptide density” refers to the percentage of monomer units in the polymer chain which have a peptide covalently linked thereto. The percentage is based on the overall sum of monomer units in the polymer chain. For example, for certain polymers described herein, each P ¹ is the polymer side chain comprising the peptide, each P ² is a polymer side chain having a composition different from that of P ¹ , and each S is independently a repeating unit having a composition different from P ¹ and P ² . Thus, the peptide density, or percentage of monomer units including the peptide (i.e., P ¹ for this particular example) would be represented by the formula: where each variable refers to the number of monomer units of that type in the polymer chain. In some embodiments, polymers of the present disclosure have a peptide density greater than or equal to 50% (e.g., greater than or equal to 55%, greater than or equal to 60%, greater than or equal to 65%, greater than or equal to 70%, greater than or equal to 75%, greater than or equal to 80%, greater than or equal to 85%, greater than or equal to 90%, or greater than or equal to 95%). In some embodiments, polymers of the present disclosure have a peptide density greater than or equal to 70%. In some embodiments, polymers of the present disclosure have a peptide density greater than or equal to 90%. In some embodiments, polymers of the present disclosure have a peptide density from 50% to 100%, 55% to 100%, 60% to 100%, 65% to 100%, 70% to 100%, 75% to 100%, 80% to 100%, 85% to 100%, 90% to 100%, 95% to 100%, 50% to 90%, 55% to 90%, 60% to 90%, 65% to 90%, 70% to 90%, 75% to 90%, 80% to 90%, 85% to 90%, 50% to 80%, 55% to 80%, 60% to 80%, 65% to 80%, 70% to 80%, 75% to 80%, 50% to 70%, 55% to 70%, 60% to 70%, 65% to 70%, 50% to 60%, or 55% to 60%. In some embodiments, the brush density is equal to the peptide density.

[0047] In some embodiments, the polymer side chain groups can have any suitable spacing on the polymer backbone. For example, in some embodiments, the space between adjacent polymer side chain groups is from 3 angstroms to 30 angstroms, 4 angstroms to 30 angstroms, 5 angstroms to 30 angstroms, 6 angstroms to 30 angstroms, 7 angstroms to 30 angstroms, 8 angstroms to 30 angstroms, 9 angstroms to 30 angstroms, 10 angstroms to 30 angstroms, 15 angstroms to 30 angstroms, 20 angstroms to 30 angstroms, 25 angstroms to 30 angstroms, 4 angstroms to 20 angstroms, 5 angstroms to 20 angstroms, 6 angstroms to 20 angstroms, 7 angstroms to 20 angstroms, 8 angstroms to 20 angstroms, 9 angstroms to 20 angstroms, 10 angstroms to 20 angstroms, 15 angstroms to 20 angstroms, 4 angstroms to 10 angstroms, 5 angstroms to 10 angstroms, 6 angstroms to 10 angstroms, 7 angstroms to 10 angstroms, 8 angstroms to 10 angstroms, or 9 angstroms to 10 angstroms. In some embodiments having a brush density of 100%, the polymer side chain groups are spaced about 6 ± 5 angstroms apart on the polymer backbone. In some embodiments, the brush polymer has a high a brush density (e.g., greater than 70%), and the polymer side chain groups are spaced about 5 to 20 angstroms apart on the polymer backbone.

[0048] The term “sequence homology” or “sequence identity” means the proportion of amino acid matches between two amino acid sequences. When sequence homology is expressed as a percentage, e.g., 50%, the percentage denotes the fraction of matches over the length of sequence that is compared to some other sequence. Gaps (in either of the two sequences) are permitted to maximize matching; for example, wherein gap lengths of 5 amino acids or less, optionally 3 amino acids or less, are usually used. In other words, a sequence having 85% or greater sequence identity of SEQ ID NO: 1 (ILWRQDIDLGVSREV) or SEQ ID NO:2 (LDPETGEFL) can indicate that the foregoing sequences can have one or two point mutations (i.e., amino acid change), one or two amino acid deletions, one or two amino acid additions, one point mutation and one amino acid deletion, or one point mutation and one amino acid addition. Similarly, a sequence having 90% or greater sequence identity of SEQ ID NO: 1 (ILWRQDIDLGVSREV) or SEQ ID NO:2 (LDPETGEFL) indicates that the foregoing sequences can have one point mutation (i.e., amino acid change), one amino acid deletion, or one amino acid addition.

[0049] The term “substantial identity” or “substantially identical,” as used in the context of polynucleotide or polypeptide sequences, refers to a sequence that has at least 60% sequence identity to a reference sequence. Alternatively, percent identity can be any integer from 60% to 100%. Exemplary embodiments include at least: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, as compared to a reference sequence using the programs described herein; preferably BLAST using standard parameters, as described below. One of skill will recognize that these values can be appropriately adjusted to determine corresponding identity of proteins encoded by two nucleotide sequences by taking into account codon degeneracy, amino acid similarity, reading frame positioning and the like.

[0050] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.

[0051] Algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1990) J. Mol. Biol. 215: 403-410 and Altschul et al. (1977) Nucleic Acids Res. 25: 3389-3402, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (NCBI) web site. The algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al, supra). These initial neighborhood word hits acts as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word size (W) of 28, an expectation (E) of 10, M=l, N=-2, and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word size (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89: 10915 (1989)).

[0052] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. Nat'l. Acad. Sci. USA 90:5873- 5787 (1993)). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.01, more preferably less than about 10' ⁵ , and most preferably less than about IO' ²⁰ .

[0053] The term “fragment” refers to a portion, but not all of, a composition or material, such as a peptide composition or material. In some embodiments, a fragment of a peptide refers to 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% of more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more of a full-length sequence of amino acids.

[0054] As used herein, the phrase “charge modulating domain” refers to one or more amino acids added to the peptide sequences described herein to modulate the charge of the peptide. For example, the charge modulating domain can be a TAT sequence, a glycineserine domain, a cationic residue domain, or a combination thereof. In some embodiments, the charge modulating domain has from 2 to 7 amino acid residues. The 2 to 7 amino acids can be added in a single block containing from 2 to 7 amino acid residues or more than one block containing from 1 to 6 amino acid residues. In some embodiments, the charge modulating domain is a cationic residue domain having from 2 to 7 amino acid residues selected from lysine, arginine, histidine, or a combination thereof. Generally, the charge modulating domain modulates the charge of the peptide to have a net positive charge. Without wishing to be bound by any particular theory, it is believed that the net positive charge increases the cellular uptake of the peptide or polymer comprising the peptide. The overall charge of the peptide or polymer comprising the peptide can be determined by any suitable means. For example, the overall charge can be determined by (i) structural analysis of the functional residues on the peptide sequence and their respective pKa, (ii) physical characterization by measuring the zeta potential, and/or (iii) by virtue of the material moving towards a negative pole in an electrophoresis polymer gel. In some embodiments, the overall charge of the peptide or polymer comprising the peptide is determined by measuring the zeta potential.

[0055] “Polymer blend” refers to a mixture including at least one polymer, such as a brush polymer, e.g., brush block copolymer or brush random copolymer, and at least one additional component, and optionally more than one additional component. In some embodiments, a polymer blend of the disclosure includes a first brush copolymer and one or more additional brush polymers having a composition different than the first brush copolymer. In some embodiments, a polymer blend of the disclosure further includes one or more additional brush block copolymers, brush random copolymers, homopolymers, copolymers, block copolymers, random copolymers, brush block copolymers, oligomers, solvent, small molecules (e.g., molecular weight less than 500 Da, optionally less than 100 Da), or any combination of these. Polymer blends useful for some applications are composed of a first brush polymer, and one or more additional components including polymers, block copolymers, brush polymers, linear block copolymers, random copolymers, homopolymers, or any combinations of these. Polymer blends of the disclosure include mixtures of two, three, four, five and more polymer components.

[0056] As used herein, the term “compound” refers to any of the peptides or polymers described herein. Alternatively, or additionally, the term compound can refer to any of the synthetic precursors, reagents, additives, excipients, etc. used in preparation of or formulation with the peptides or polymers described herein.

[0057] As used herein, the term “group” refers to a functional group of a chemical compound. Groups of the present compounds refer to an atom or a collection of atoms that are a part of the compound. Groups of the present disclosure may be attached to other atoms of the compound via one or more covalent bonds. Groups may also be characterized with respect to their valence state. The present disclosure includes groups characterized as monovalent, divalent, trivalent, etc. valence states.

[0058] As used herein, the term “substituted” refers to a compound wherein a functional group is replaced by another, different functional group.

[0059] Unless otherwise specified, the term “average molecular weight,” refers to the number average molecular weight. Number average molecular weight is defined as the total weight of a sample volume divided by the number of molecules within the sample. As is customary and well known in the art, peak average molecular weight and weight average molecular weight may also be used to characterize the molecular weight of the distribution of polymers within a sample.

[0060] As is customary and well known in the art, hydrogen atoms in formulas are not always explicitly shown, for example, hydrogen atoms bonded to the carbon atoms of aromatic, heteroaromatic, and alicyclic rings are not always explicitly shown in any one of Formula I to Formula VII. The structures provided herein, for example in the context of the description of Formula I to Formula VII and schematics and structures in the drawings, are intended to convey to one of reasonable skill in the art, the chemical composition of compounds of the methods and compositions, and as will be understood by one of skill in the art, the structures provided do not indicate the specific positions and/or orientations of atoms and the corresponding bond angles between atoms of these compounds.

[0061] As used herein, the terms “alkylene” and “alkylene group” are used synonymously and refer to a divalent group derived from an alkyl group as defined herein. Compounds disclosed herein may have one or more alkylene groups. Alkylene groups in some compounds function as linking and/or spacer groups. Compounds disclosed herein may have substituted and/or unsubstituted C1-C20 alkylene, C1-C10 alkylene and C1-C5 alkylene groups, for example, as one or more linking groups (e.g., L ¹ - L ² ).

[0062] As used herein, the terms “cycloalkylene” and “cycloalkylene group” are used synonymously and refer to a divalent group derived from a cycloalkyl group as defined herein. Compounds disclosed herein may have one or more cycloalkylene groups. Cycloalkyl groups in some compounds function as linking and/or spacer groups. Compounds disclosed herein may have substituted and/or unsubstituted C3-C20 cycloalkylene, C3-C10 cycloalkylene and C3-C5 cycloalkylene groups, for example, as one or more linking groups (e.g., L ¹ - L ² ).

[0063] As used herein, the terms “arylene” and “arylene group” are used synonymously and refer to a divalent group derived from an aryl group as defined herein. Compounds disclosed herein may have one or more arylene groups. In some embodiments, an arylene is a divalent group derived from an aryl group by removal of hydrogen atoms from two intra-ring carbon atoms of an aromatic ring of the aryl group. Arylene groups in some compounds function as linking and/or spacer groups. Arylene groups in some compounds function as chromophore, fluorophore, aromatic antenna, dye and/or imaging groups. Compounds disclosed herein may include substituted and/or unsubstituted C3-C30 arylene, C3-C20 arylene, C3-C10 arylene and C1-C5 arylene groups, for example, as one or more linking groups (e.g., L ¹ - L ² ).

[0064] As used herein, the terms “heteroarylene” and “heteroarylene group” are used synonymously and refer to a divalent group derived from a heteroaryl group as defined herein. Compounds disclosed herein may include one or more heteroarylene groups. In some embodiments, a heteroarylene is a divalent group derived from a heteroaryl group by removal of hydrogen atoms from two intra-ring carbon atoms or intra-ring nitrogen atoms of a heteroaromatic or aromatic ring of the heteroaryl group. Heteroarylene groups in some compounds function as linking and/or spacer groups. Heteroarylene groups in some compounds function as chromophore, aromatic antenna, fluorophore, dye and/or imaging groups. Compounds disclosed herein may include substituted and/or unsubstituted C3-C30 heteroarylene, C3- C20 heteroarylene, Ci-C 10 heteroarylene and C 3 -C 5 heteroarylene groups, for example, as one or more linking groups (e.g., L ¹ - L ² ).

[0065] As used herein, the terms “alkenylene” and “alkenylene group” are used synonymously and refer to a divalent group derived from an alkenyl group as defined herein. Compounds disclosed herein may include one or more alkenylene groups. Alkenylene groups in some compounds function as linking and/or spacer groups. Compounds disclosed herein may include substituted and/or unsubstituted C2-C20 alkenylene, C2-C10 alkenylene and C2-C5 alkenylene groups, for example, as one or more linking groups (e.g., L ¹ - L ² ).

[0066] As used herein, the terms “cycloalkenylene” and “cycloalkenylene group” are used synonymously and refer to a divalent group derived from a cycloalkenyl group as defined herein. Compounds disclosed herein may include one or more cycloalkenylene groups. Cycloalkenylene groups in some compounds function as linking and/or spacer groups. Compounds disclosed herein may include substituted and/or unsubstituted C3-C20 cycloalkenylene, C3-C10 cycloalkenylene and C3-C5 cycloalkenylene groups, for example, as one or more linking groups (e.g., L ¹ - L ² ).

[0067] As used herein, the terms “alkynylene” and “alkynylene group” are used synonymously and refer to a divalent group derived from an alkynyl group as defined herein. Compounds disclosed herein may include one or more alkynylene groups. Alkynylene groups in some compounds function as linking and/or spacer groups. Compounds disclosed herein may include substituted and/or unsubstituted C2-C20 alkynylene, C2-C10 alkynylene and C2-C5 alkynylene groups, for example, as one or more linking groups (e.g., L ¹ - L ² ).

[0068] As used herein, the term “halo” refers to a halogen group such as a fluoro (-F), chloro (-C1), bromo (-Br), iodo (-1) or astato (-At).

[0069] The term “heterocyclic” refers to ring structures containing at least one other kind of atom, in addition to carbon, in the ring. Examples of such heteroatoms include nitrogen, oxygen and sulfur. Heterocyclic rings include heterocyclic alicyclic rings and heterocyclic aromatic rings. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, piperidyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrazinyl, indolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, benzoxadiazolyl, benzothiadiazolyl, triazolyl and tetrazolyl groups. Atoms of heterocyclic rings can be bonded to a wide range of other atoms and functional groups, for example, provided as substituents.

[0070] The term “carbocyclic” refers to ring structures containing only carbon atoms in the ring. Carbon atoms of carbocyclic rings can be bonded to a wide range of other atoms and functional groups, for example, provided as substituents.

[0071] The term “aromatic ring” refers to a ring, or a plurality of fused rings, that includes at least one aromatic ring group. The term aromatic ring includes aromatic rings including carbon, hydrogen and heteroatoms. Aromatic rings include carbocyclic and heterocyclic aromatic rings. Aromatic rings are components of aryl groups.

[0072] The term “fused ring” or “fused ring structure” refers to a plurality of alicyclic and/or aromatic rings provided in a fused ring configuration, such as fused rings that share at least two intra ring carbon atoms and/or heteroatoms.

[0073] As used herein, the term “alkoxyalkyl” refers to a substituent of the formula alkyl- O-alkyl.

[0074] As used herein, the term “polyhydroxyalkyl” refers to a substituent having from 2 to 12 carbon atoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4- trihydroxybutyl or 2,3,4,5-tetrahydroxypentyl residue.

[0075] As used herein, the term “polyalkoxyalkyl” refers to a substituent of the formula alkyl-(alkoxy)n-alkoxy wherein n is an integer from 1 to 10, preferably 1 to 4, and more preferably for some embodiments 1 to 3.

[0076] Amino acids include the 20 common amino acids: glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, asparagine, glutamine, serine, threonine, tyrosine, cysteine, lysine, arginine, histidine, aspartic acid and glutamic acid. As used herein, reference to “a side chain residue of a natural a-amino acid” specifically includes the side chains of the above-referenced amino acids. Peptides are comprised of two or more amino acids connected via peptide bonds. In some embodiments, amino acids include non-natural amino acids. As used herein, “non-natural amino acids” are amino acids that are not genetically encoded and are not one of the 20 common amino acids, pyrolysine, or selenocysteine. Non-natural amino acids can include, but are not limited to, D-amino acids (e.g., D-Arg), analogs of natural amino acids with modified side chain or backbones, L- citrulline, azidohomoalanine, N-acetylglucosaminyl-L-serine, N-acetylglucosaminyl-L- threonine, and O-phosphotyrosine.

[0077] Alkyl groups include straight-chain, branched and cyclic alkyl groups. Alkyl groups include those having from 1 to 30 carbon atoms. Alkyl groups include small alkyl groups having 1 to 3 carbon atoms. Alkyl groups include medium length alkyl groups having from 4-10 carbon atoms. Alkyl groups include long alkyl groups having more than 10 carbon atoms, particularly those having 10-30 carbon atoms. The term cycloalkyl specifically refers to an alky group having a ring structure such as ring structure including 3-30 carbon atoms, optionally 3-20 carbon atoms and optionally 2-10 carbon atoms, including an alkyl group having one or more rings. Cycloalkyl groups include those having 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-member carbon ring(s) and particularly those having a 3-, 4-, 5-, 6-, or 7-member ring(s). The carbon rings in cycloalkyl groups can also carry alkyl groups. Cycloalkyl groups can include bicyclic and tricycloalkyl groups. Alkyl groups are optionally substituted. Substituted alkyl groups include among others those which are substituted with aryl groups, which in turn can be optionally substituted. Specific alkyl groups include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, branched-pentyl, cyclopentyl, n-hexyl, branched hexyl, and cyclohexyl groups, all of which are optionally substituted. Substituted alkyl groups include fully halogenated or semihalogenated alkyl groups, such as alkyl groups having one or more hydrogens replaced with one or more fluorine atoms, chlorine atoms, bromine atoms and/or iodine atoms. Substituted alkyl groups include fully fluorinated or semifluorinated alkyl groups, such as alkyl groups having one or more hydrogens replaced with one or more fluorine atoms. An alkoxy group is an alkyl group that has been modified by linkage to oxygen and can be represented by the formula R-0 and can also be referred to as an alkyl ether group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy and heptoxy. Alkoxy groups include substituted alkoxy groups wherein the alky portion of the groups is substituted as provided herein in connection with the description of alkyl groups. As used herein MeO- refers to CH3O-. Compositions of some embodiments of the disclosure include alkyl groups as terminating groups, such as polymer backbone terminating groups and/or polymer side chain terminating groups.

[0078] Alkenyl groups include straight-chain, branched and cyclic alkenyl groups. Alkenyl groups include those having 1, 2 or more double bonds and those in which two or more of the double bonds are conjugated double bonds. Alkenyl groups include those having from 2 to 20 carbon atoms. Alkenyl groups include small alkenyl groups having 2 to 3 carbon atoms. Alkenyl groups include medium length alkenyl groups having from 4-10 carbon atoms. Alkenyl groups include long alkenyl groups having more than 10 carbon atoms, particularly those having 10-20 carbon atoms. Cycloalkenyl groups include those in which a double bond is in the ring or in an alkenyl group attached to a ring. The term cycloalkenyl specifically refers to an alkenyl group having a ring structure, including an alkenyl group having 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- member carbon ring(s) and particularly those having 3-, 4-, 5-, 6- or 7-member ring(s). The carbon rings in cycloalkenyl groups can also carry alkyl groups. Cycloalkenyl groups can include bicyclic and tricyclic alkenyl groups. Alkenyl groups are optionally substituted. Substituted alkenyl groups include, among others, those which are substituted with alkyl or aryl groups, which groups in turn can be optionally substituted. Specific alkenyl groups include ethenyl, prop-l-enyl, prop-2-enyl, cycloprop- 1- enyl, but-l-enyl, but-2-enyl, cyclobut-l-enyl, cyclobut-2-enyl, pent-l-enyl, pent-2-enyl, branched pentenyl, cyclopent- 1-enyl, hex-l-enyl, branched hexenyl, cyclohexenyl, all of which are optionally substituted. Substituted alkenyl groups include fully halogenated or semihalogenated alkenyl groups, such as alkenyl groups having one or more hydrogens replaced with one or more fluorine atoms, chlorine atoms, bromine atoms and/or iodine atoms. Substituted alkenyl groups include fully fluorinated or semifluorinated alkenyl groups, such as alkenyl groups having one or more hydrogen atoms replaced with one or more fluorine atoms. Compositions of some embodiments of the disclosure include alkenyl groups as terminating groups, such as polymer backbone terminating groups and/or polymer side chain terminating groups.

[0079] Aryl groups include groups having one or more 5-, 6- or 7- member aromatic rings, including heterocyclic aromatic rings. The term heteroaryl specifically refers to aryl groups having at least one 5-, 6- or 7- member heterocyclic aromatic ring. Aryl groups can contain one or more fused aromatic rings, including one or more fused heteroaromatic rings, and/or a combination of one or more aromatic rings and one or more nonaromatic rings that may be fused or linked via covalent bonds. Heterocyclic aromatic rings can include one or more N, O, or S atoms in the ring. Heterocyclic aromatic rings can include those with one, two or three N atoms, those with one or two O atoms, and those with one or two S atoms, or combinations of one or two or three N, O or S atoms. Aryl groups are optionally substituted. Substituted aryl groups include, among others, those which are substituted with alkyl or alkenyl groups, which groups in turn can be optionally substituted. Specific aryl groups include phenyl, biphenyl groups, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrazinyl, indolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, benzoxadiazolyl, benzothiadiazolyl, and naphthyl groups, all of which are optionally substituted. Substituted aryl groups include fully halogenated or semihalogenated aryl groups, such as aryl groups having one or more hydrogens replaced with one or more fluorine atoms, chlorine atoms, bromine atoms and/or iodine atoms. Substituted aryl groups include fully fluorinated or semifluorinated aryl groups, such as aryl groups having one or more hydrogens replaced with one or more fluorine atoms. Aryl groups include, but are not limited to, aromatic group- containing or heterocylic aromatic group-containing groups corresponding to any one of the following: benzene, naphthalene, naphthoquinone, diphenylmethane, fluorene, anthracene, anthraquinone, phenanthrene, tetracene, tetracenedione, pyridine, quinoline, isoquinoline, indoles, isoindole, pyrrole, imidazole, oxazole, thiazole, pyrazole, pyrazine, pyrimidine, purine, benzimidazole, furans, benzofuran, dibenzofuran, carbazole, acridine, acridone, phenanthridine, thiophene, benzothiophene, dibenzothiophene, xanthene, xanthone, flavone, coumarin, azulene or anthracycline. As used herein, a group corresponding to the groups listed above expressly includes an aromatic or heterocyclic aromatic group, including monovalent, divalent and polyvalent groups, of the aromatic and heterocyclic aromatic groups listed herein are provided in a covalently bonded configuration in the compounds of the disclosure at any suitable point of attachment. In embodiments, aryl groups contain between 5 and 30 carbon atoms. In embodiments, aryl groups contain one aromatic or heteroaromatic six-membered ring and one or more additional five- or six-membered aromatic or heteroaromatic ring. In embodiments, aryl groups contain between five and eighteen carbon atoms in the rings. Aryl groups optionally have one or more aromatic rings or heterocyclic aromatic rings having one or more electron donating groups, electron withdrawing groups and/or targeting ligands provided as substituents. Compositions of some embodiments of the disclosure include aryl groups as terminating groups, such as polymer backbone terminating groups and/or polymer side chain terminating groups.

[0080] Arylalkyl groups are alkyl groups substituted with one or more aryl groups wherein the alkyl groups optionally carry additional substituents and the aryl groups are optionally substituted. Specific alkylaryl groups are phenyl -substituted alkyl groups, e.g., phenylmethyl groups. Alkylaryl groups are alternatively described as aryl groups substituted with one or more alkyl groups wherein the alkyl groups optionally carry additional substituents and the aryl groups are optionally substituted. Specific alkylaryl groups are alkyl-substituted phenyl groups such as methylphenyl. Substituted arylalkyl groups include fully halogenated or semihalogenated arylalkyl groups, such as arylalkyl groups having one or more alkyl and/or aryl groups having one or more hydrogens replaced with one or more fluorine atoms, chlorine atoms, bromine atoms and/or iodine atoms. Compositions of some embodiments of the disclosure include arylalkyl groups as terminating groups, such as polymer backbone terminating groups and/or polymer side chain terminating groups.

[0081] As to any of the groups described herein which contain one or more substituents, it is understood that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. Optional substitution of alkyl groups includes substitution with one or more alkenyl groups, aryl groups or both, wherein the alkenyl groups or aryl groups are optionally substituted. Optional substitution of alkenyl groups includes substitution with one or more alkyl groups, aryl groups, or both, wherein the alkyl groups or aryl groups are optionally substituted. Optional substitution of aryl groups includes substitution of the aryl ring with one or more alkyl groups, alkenyl groups, or both, wherein the alkyl groups or alkenyl groups are optionally substituted.

[0082] Optional substituents for any alkyl, alkenyl and aryl group includes substitution with one or more of the following substituents, among others: halogen, including fluorine, chlorine, bromine or iodine; and pseudohalides, including:

-CN;

-COOR where R is a hydrogen or an alkyl group or an aryl group and more specifically where R is a methyl, ethyl, propyl, butyl, or phenyl group all of which groups are optionally substituted;

-COR where R is a hydrogen or an alkyl group or an aryl group and more specifically where R is a methyl, ethyl, propyl, butyl, or phenyl group all of which groups are optionally substituted;

-CON(R)2 where each R, independently of each other R, is a hydrogen or an alkyl group or an aryl group and more specifically where R is a methyl, ethyl, propyl, butyl, or phenyl group all of which groups are optionally substituted; and where R and R can form a ring which can contain one or more double bonds and can contain one or more additional carbon atoms;

-OCON(R)2 where each R, independently of each other R, is a hydrogen or an alkyl group or an aryl group and more specifically where R is a methyl, ethyl, propyl, butyl, or phenyl group all of which groups are optionally substituted; and where R and R can form a ring which can contain one or more double bonds and can contain one or more additional carbon atoms;

-N(R)2 where each R, independently of each other R, is a hydrogen, or an alkyl group, or an acyl group or an aryl group and more specifically where R is a methyl, ethyl, propyl, butyl, phenyl or acetyl group, all of which are optionally substituted; and where R and R can form a ring which can contain one or more double bonds and can contain one or more additional carbon atoms;

-SR, where R is hydrogen or an alkyl group or an aryl group and more specifically where R is hydrogen, methyl, ethyl, propyl, butyl, or a phenyl group, which are optionally substituted;

-SO2R, or -SOR where R is an alkyl group or an aryl group and more specifically where R is a methyl, ethyl, propyl, butyl, or phenyl group, all of which are optionally substituted;

-OCOOR where R is an alkyl group or an aryl group;

-SO ₂ N(R)2 where each R, independently of each other R, is a hydrogen, or an alkyl group, or an aryl group all of which are optionally substituted and wherein R and R can form a ring which can contain one or more double bonds and can contain one or more additional carbon atoms; and

-OR where R is H, an alkyl group, an aryl group, or an acyl group all of which are optionally substituted. In a particular example R can be an acyl yielding -OCOR” where R” is a hydrogen or an alkyl group or an aryl group, and more specifically where R” is methyl, ethyl, propyl, butyl, or phenyl groups, all of which groups are optionally substituted.

[0083] Specific substituted alkyl groups include haloalkyl groups, particularly trihalomethyl groups and specifically trifluoromethyl groups. Specific substituted aryl groups include mono-, di-, tri, tetra- and pentahalo-substituted phenyl groups; mono-, di-, tri-, tetra-, penta-, hexa-, and hepta-halo-substituted naphthalene groups; 3- or 4-halo-substituted phenyl groups, 3- or 4-alkyl-substituted phenyl groups, 3- or 4-alkoxy-substituted phenyl groups, 3- or 4-RCO-substituted phenyl, 5- or 6-halo-substituted naphthalene groups. More specifically, substituted aryl groups include acetylphenyl groups, particularly 4-acetylphenyl groups; fluorophenyl groups, particularly 3 -fluorophenyl and 4-fluorophenyl groups; chlorophenyl groups, particularly 3 -chlorophenyl and 4-chlorophenyl groups; methylphenyl groups, particularly 4-methylphenyl groups; and methoxyphenyl groups, particularly 4- methoxyphenyl groups. [0084] As to any of the above groups which contain one or more substituents, it is understood that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.

[0085] The term “pharmaceutically acceptable salts” refers to salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium salt, or a similar salt. When compounds disclosed herein contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present disclosure. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, which is combined with buffer prior to use.

[0086] Thus, the compounds disclosed herein may exist as salts, such as with pharmaceutically acceptable acids. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

[0087] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0088] In addition to salt forms, compounds disclosed herein may be in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds. Additionally, prodrugs can be converted to the compounds disclosed herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0089] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0090] As used herein, the term “salt” refers to acid or base salts of the compounds used in the methods of the present disclosure. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

[0091] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (A)- or (5)- or, as D- or L- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those which are known in the art to be too unstable to synthesize and/or isolate. The present disclosure includes compounds in racemic and optically pure forms. Optically active (A)- and (5 -, or D- or L -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0092] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. Isomers include structural isomers and stereoisomers such as enantiomers.

[0093] The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0094] It will be apparent to one skilled in the art that certain compounds may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the present disclosure.

[0095] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds are within the scope of the present disclosure.

[0096] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the present disclosure.

[0097] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0098] The symbol “ ' rw' denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula. [0099] The terms “treating” or “treatment” refer to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to a subject, such as a patient in need of treatment; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a subject's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. As used herein, the terms “treating” or “treatment” include management, slowing the progression, and abating the symptoms of a disease, pathology or condition.

[0100] An “effective amount” is an amount sufficient to accomplish a stated purpose (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce transcriptional activity, increase transcriptional activity, reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist (inhibitor) required to decrease the activity of an enzyme or protein (e.g., transcription factor) relative to the absence of the antagonist. An “activity increasing amount,” as used herein, refers to an amount of agonist (activator) required to increase the activity of an enzyme or protein (e.g., transcription factor) relative to the absence of the agonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist (inhibitor) required to disrupt the function of an enzyme or protein (e.g., transcription factor) relative to the absence of the antagonist. A “function increasing amount,” as used herein, refers to the amount of agonist (activator) required to increase the function of an enzyme or protein (e.g., transcription factor) relative to the absence of the agonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0101] As defined herein, the term “inhibition,” “inhibit,” “inhibiting,” and the like in reference to a protein-inhibitor (e.g., antagonist) interaction means negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction in binding of a protein with one or more than one cognate binding partner. In some embodiments inhibition refers to reduction of a disease or symptoms of a disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein.

[0102] As defined herein, the term “activation,” “activate,” “activating,” and the like in reference to a protein-activator (e.g., agonist) interaction means positively affecting (e.g., increasing) the activity or function of the protein.

[0103] The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule.

[0104] As used herein, the terms “patient” or “subject in need thereof’ refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a compound or pharmaceutical composition, as provided herein. Such organisms preferably include, but are not limited to, mammals (e.g., simians, murines, equines, bovines, porcines, canines, felines, and the like), and more preferably include humans. Non-limiting examples include humans, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other nonmammalian animals. In some embodiments, a patient is human. In some embodiments, a patient is a mammal. In some embodiments, a patient is a mouse. In some embodiments, a patient is an experimental animal. In some embodiments, a patient is a rat. In some embodiments, a patient is a test animal. [0105] As used herein, the terms “pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0106] The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0107] As used herein, the term “administering” means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). In some embodiments, administration includes direct administration to a tumor. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “coadminister” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anticancer agent or chemotherapeutic). The compound of the disclosure can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present disclosure can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, or aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, and suspensions, suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. The compositions disclosed herein may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 30 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions disclosed herein can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see, e.g., Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., G o Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669- 674, 1997). In another embodiment, the formulations of the compositions of the present disclosure can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present disclosure into the target cells in vivo, (see, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm .46: 1576- 1587, 1989).

[0108] As used herein, the term “conjugated” when referring to two moieties means the two moieties are bonded, wherein the bond or bonds connecting the two moieties may be covalent or non-covalent. In some embodiments, the two moieties are covalently bonded to each other (e.g., directly or through a covalently bonded intermediary). In some embodiments, the two moieties are non-covalently bonded (e.g., through ionic bond(s), van der waal's bond(s)/interactions, hydrogen bond(s), polar bond(s), or combinations or mixtures thereof).

[0109] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. The term “about,” as used herein when referring to a measurable value such as an amount of mass, weight, time, volume, concentration, or percentage, is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±9%, in some embodiments ±8%, in some embodiments ±7%, in some embodiments ±6%, in some embodiments ±5%, in some embodiments ±4%, in some embodiments ±3%, in some embodiments ±2%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods and/or employ the disclosed compositions. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.

[0110] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[OHl] As used herein, the term “sequence of equivalent coding potential” refers to a nucleic acid sequence having functional equivalence to another reference nucleic acid. A sequence of equivalent coding potential may or may not have the same primary nucleotide sequence. For example, for a reference nucleic acid coding for an expressed polypeptide, a sequence of equivalent coding potential is functionally able to code for the same expressed polypeptide and may comprise an identical primary nucleotide sequence as the reference nucleic acid, or may comprise one or more alternative codon(s) as compared to the reference nucleic acid. For example, an endogenous nucleic acid sequence encoding a polypeptide may be altered via codon optimization to result in a sequence that codes for an identical polypeptide. A codon optimized sequence may be one in which codons in a polynucleotide encoding a polypeptide have been substituted in order to modify the activity, expression, and/or stability of the polynucleotide. For example, codon optimization can be used to vary the degree of sequence similarity of a sequence of equivalent coding potential as compared to an endogenous gene sequence, while preserving the potential to encode the protein product of the endogenous gene.

[0112] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[0113] In the following description, numerous specific details of the compounds, compositions components and methods of the present disclosure are set forth in order to provide a thorough explanation of the precise nature of the disclosure.

1. Polypeptide

[0114] As used herein, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. As used herein, the terms encompass amino acid chains of any length, including full-length proteins, and functional fragments thereof, wherein the amino acid residues are linked by covalent peptide bonds.

[0115] In an aspect, provided herein is a polypeptide including a peptide having a sequence at least 88% identical (e.g., 88.8%, 93.3%, or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV) or SEQ ID NO:2 (LDPETGEFL) and a charge modulating peptide, where the polypeptide is 17 to 22 amino acids long.

[0116] As used herein, a sequence having at least 93% sequence identity to SEQ ID NO: 1 (ILWRQDIDLGVSREV) indicates that the sequence can have one point mutation (z.e., amino acid change), one amino acid deletion, or one amino acid addition. In some embodiments, the sequence having at least 93% sequence identity to SEQ ID NO: 1 (ILWRQDIDLGVSREV) is 93.3$ identical to SEQ ID NO: 1 or 100% identical to SEQ ID NO: 1 (ILWRQDIDLGVSREV).

[0117] As used herein, a sequence having at least 88% sequence identity to SEQ ID NO:2 (LDPETGEFL) indicates that the sequence can have one point mutation (z.e., amino acid change), one amino acid deletion, or one amino acid addition. In some embodiments, the sequence having at least 88% sequence identity to SEQ ID NO:2 (LDPETGEFL) is 88.8% identical to SEQ ID NO:2 or 100% identical to SEQ ID NO:2 (LDPETGEFL).

[0118] In some embodiments, the charge-modulating peptide is 2 to 7 amino acid residues long. For example, in some embodiments, the charge-modulating peptide is 2 amino acid residues, 3 amino acid residues, 4 amino acid residues, 5 amino acid residues, 6 amino acid residues, or 7 amino acid residues long. In some embodiments, the charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the N-terminus of the peptide having a sequence at least 93% identical (e.g. 93% or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV). In some embodiments an additional charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the C-terminus of the peptide having a sequence at least 93% identical (e.g. 93% or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV). In some embodiments, the charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the C-terminus of the peptide having a sequence at least 93% identical (e.g., 93% or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV). In some embodiments an additional charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the N-terminus of the peptide having a sequence at least 93% identical (e.g. 93% or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV).

[0119] In some embodiments, the charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the N-terminus of the peptide having a sequence at least 88% identical (e.g. 88.8% or 100% identical) to SEQ ID NO:2 (LDPETGEFL). In some embodiments an additional charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the C- terminus of the peptide having a sequence at least 88% identical (e.g. 88.8% or 100% identical) to SEQ ID NO:2 (LDPETGEFL). In some embodiments, the charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the C-terminus of the peptide having a sequence at least 88% identical (e.g., 88.8% or 100% identical) to SEQ ID NO:2 (LDPETGEFL). In some embodiments an additional charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the N-terminus of the peptide having a sequence at least 88% identical (e.g. 88.8% or 100% identical) to SEQ ID NO:2 (LDPETGEFL).

[0120] In some embodiments, the additional charge-modulating peptide is 2 to 7 amino acid residues long. For example, in some embodiments, the additional charge-modulating peptide is 2 amino acid residues, 3 amino acid residues, 4 amino acid residues, 5 amino acid residues, 6 amino acid residues, or 7 amino acid residues long. [0121] In some embodiments, the charge-modulating peptide and/or additional chargemodulating peptide is a glycine-serine domain, a cationic residue domain, or a combination thereof. In certain embodiments, the charge-modulating peptide and/or additional chargemodulating peptide is a cationic residue peptide having from 2 to 7 amino acid residues selected from lysine, arginine, histidine, and a combination thereof.

[0122] In some embodiments, the charge-modulating peptide and/or additional charge modulating peptide is a combination of D-arginine (r) and L-arginine (R). For example, in some embodiments the charge-modulating peptide and/or additional charge modulating peptide includes a sequence of RrRr (SEQ ID NO: 607), rRrR (SEQ ID NO: 608), rrRR (SEQ ID NO: 609), RRrr (SEQ ID NO: 610), RrrR (SEQ ID NO: 611), or rRRr (SEQ ID NO: 612). In some embodiments, polypeptides of the present disclosure include a D-arginine and L- arginine containing charge-modulating peptide covalently linked (e.g., via a peptide bond) to the C-terminus of the peptide having a sequence at least 93% identical (e.g., 93% or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV). In some embodiments, polypeptides of the present disclosure include a D-arginine and L-arginine containing charge-modulating peptide covalently linked (e.g., via a peptide bond) to the C-terminus of the peptide having a sequence at least 88% identical (e.g. 88.8% or 100% identical) to SEQ ID NO:2 (LDPETGEFL). In some embodiments, D-arginine or L-arginine residues are substituted with L-citrulline.

[0123] In some embodiments, the charge-modulating peptide and/or additional charge modulating peptide incorporates a histidine tag (e.g, HHHHHHH (SEQ ID NO:593); or HHHHHH (SEQ ID NO:594). In some embodiments, the histidine tag is covalently linked (e.g, via a peptide bond) to the N-terminus or C-terminus of the peptide having a sequence at least 93% identical (e.g., 93% or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV). In some embodiments, the histidine tag is covalently linked (e.g., via a peptide bond) to the N-terminus or C-terminus of the peptide having a sequence at least 88% identical (e.g. 88.8% or 100% identical) to SEQ ID NO:2 (LDPETGEFL).

[0124] In some embodiments, the polypeptide has a net positive charge. Without wishing to be bound by any particular theory, it is believed that the net positive charge increases the cellular uptake of the peptide or polymer comprising the peptide. Additionally, the addition of residues to form a net positive charge may enhance the aqueous solubility of the compound to facilitate therapeutic use.

[0125] In some embodiments, the polypeptide comprises a sequence 100% identical to any one of SEQ ID NOs:3 to 592 (see TABLE 1). TABLE 1 -NRF2 POLYPEPTIDE SEQUENCES

2. Protein-Like Polymers

[0126] In another aspect, provided herein is a polymer including a first polymer segment comprising at least two first repeating units, where each of the first repeating units has a first polymer backbone group directly or indirectly covalently linked to a first polymer side chain group comprising a peptide having a sequence at least 93% identical (e.g., 93.3% or 100%) to SEQ ID NO: 1 (ILWRQDIDLGVSREV) or at least 88% identical (e.g., 88.8% or 100%) to SEQ ID NO:2 (LDPETGEFL). In some embodiments, the peptide has a sequence 100% identical to SEQ ID NO: 1 (ILWRQDIDLGVSREV) or SEQ ID NO:2 (LDPETGEFL).

[0127] A polymer of the present disclosure can be any suitable polymer type described herein and can include, or be derived from, any suitable number of monomers. In some embodiments, the polymer is a homopolymer (e.g., derived from one type of monomer). In some embodiments, the polymer can be a copolymer having (e.g., derived from) more than one type of monomer e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10 types of monomers). It will be understood that a polymer of the present disclosure, along with the linked polymer side chains, can have any suitable configuration. In some embodiments, where the polymer is a homopolymer, the polymer can be a brush polymer. In some embodiments, where the polymer is a copolymer, the polymer can be a brush block copolymer or brush random copolymer.

[0128] In some embodiments, a polymer of the present disclosure is composed of a first polymer segment including at least 2 first repeating units (e.g., 2 to 30, 3 to 30, 4 to 30, 5 to 30, 6 to 30, 7 to 30, 8 to 30, 9 to 30, 10 to 30, 15 to 30, 20 to 30, 25 to 30, 2 to 25, 3 to 25, 4 to 25, 5 to 25, 6 to 25, 7 to 25, 8 to 25, 9 to 25, 10 to 25, 15 to 25, 20 to 25, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 15 to 20, 2 to 15, 3 to 15, 4 to 15, 5 to 15, 6 to 15, 7 to 15, 8 to 15, 9 to 15, 10 to 15, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to

10, 8 to 10, 9 to 10, 2 to 5, 3 to 5, or 4 to 5 first repeating units); where each of the first repeating units of the first polymer segment includes a first polymer backbone group directly or indirectly covalently linked to a first polymer side chain group composed of a polypeptide (e.g., a therapeutic polypeptide) including a sequence having at least 93% (e.g., 93.3% or 100%) sequence identity to SEQ ID NO: 1 (ILWRQDIDLGVSREV), or at least 88% (e.g., 88.8% or 100%) sequence identity to SEQ ID NO:2 (LDPETGEFL).

[0129] In some embodiments, a polymer of the present disclosure includes a first polymer segment having at least 5 first repeating units; where each of the first repeating units of the first polymers comprises a first polymer backbone group directly or indirectly covalently linked to a first polymer side chain group comprising a peptide; wherein the peptide comprises a sequence having at least 93% (e.g., 93.3% or 100%) sequence identity to SEQ ID NO: 1 (ILWRQDIDLGVSREV), or at least 88% (e.g., 88.8% or 100%) sequence identity to SEQ ID NO:2 (LDPETGEFL). In some embodiments, the polymer can be any suitable polymer type described herein and can comprise, or be derived from, any suitable number of monomers. For example, in some embodiments, the polymer is a homopolymer (i.e. derived from one type of monomer).

[0130] In some embodiments, the first polymer side chain group further comprises a charge-modulating peptide. In some embodiments, the charge-modulating peptide is a glycine-serine peptide, a cationic residue peptide, or a combination thereof. In some embodiments, the cationic residue peptide comprises lysine, arginine, histidine, or a combination thereof. In some embodiments, the charge-modulating peptide of the first polymer side chain group is 2 to 7 amino acid residues long. For example, in some embodiments, the charge-modulating peptide of the first polymer side chain group is 2 amino acid residues, 3 amino acid residues, 4 amino acid residues, 5 amino acid residues, 6 amino acid residues, or 7 amino acid residues long. In some embodiments, the charge-modulating peptide of the first polymer side chain group is covalently linked (e.g., via a peptide bond) to the N-terminus of the peptide having a sequence at least 93% identical (e.g. 93.3% or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV). In some embodiments an additional charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the C-terminus of the peptide having a sequence at least 93% identical (e.g 93.3% or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV). In some embodiments, the charge-modulating peptide is covalently linked (e.g, via a peptide bond) to the C-terminus of the peptide having a sequence at least 93% identical (e.g. 93.3% or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV). In some embodiments an additional charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the N-terminus of the peptide having a sequence at least 93% identical (e.g. 93.3% or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV).

[0131] In some embodiments, the charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the N-terminus of the peptide having a sequence at least 88% identical (e.g. 88.8% or 100% identical) to SEQ ID NO:2 (LDPETGEFL). In some embodiments an additional charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the C- terminus of the peptide having a sequence at least 88% identical (e.g. 88.8% or 100% identical) to SEQ ID NO:2 (LDPETGEFL). In some embodiments, the charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the C-terminus of the peptide having a sequence at least 88% identical (e.g., 88.8% or 100% identical) to SEQ ID NO:2 (LDPETGEFL). In some embodiments an additional charge-modulating peptide is covalently linked (e.g., via a peptide bond) to the N-terminus of the peptide having a sequence at least 88% identical (e.g. 88.8% or 100% identical) to SEQ ID NO:2 (LDPETGEFL).

[0132] In some embodiments, the additional charge-modulating peptide is 2 to 7 amino acid residues long. For example, in some embodiments, the additional charge-modulating peptide is 2 amino acid residues, 3 amino acid residues, 4 amino acid residues, 5 amino acid residues, 6 amino acid residues, or 7 amino acid residues long.

[0133] In some embodiments, the charge-modulating peptide and/or additional chargemodulating peptide of the first polymer side chain group is a glycine-serine domain, a cationic residue domain, or a combination thereof. In certain embodiments, the charge- modulating peptide and/or additional charge-modulating peptide is a cationic residue peptide having from 2 to 7 amino acid residues selected from lysine, arginine, histidine, and a combination thereof.

[0134] In some embodiments, the charge-modulating peptide and/or additional charge modulating peptide is a combination of D-arginine (r) and L-arginine (R). For example, in some embodiments the charge-modulating peptide and/or additional charge modulating peptide includes a sequence of RrRr (SEQ ID NO: 607), rRrR (SEQ ID NO: 608), rrRR (SEQ ID NO: 609), RRrr (SEQ ID NO: 610), RrrR (SEQ ID NO: 611), or rRRr (SEQ ID NO: 612). In some embodiments, polypeptides of the present disclosure include a D-arginine and L- arginine containing charge-modulating peptide covalently linked (e.g., via a peptide bond) to the C-terminus of the peptide having a sequence at least 93% identical (e.g., 93% or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV). In some embodiments, polypeptides of the present disclosure include a D-arginine and L-arginine containing charge-modulating peptide covalently linked (e.g., via a peptide bond) to the C-terminus of the peptide having a sequence at least 88% identical (e.g. 88.8% or 100% identical) to SEQ ID NO:2 (LDPETGEFL). In some embodiments, D-arginine or L-arginine residues are substituted with L-citrulline.

[0135] In some embodiments, the charge-modulating peptide and/or additional charge modulating peptide of the first polymer side chain group incorporates a histidine tag (e.g, HHHHHHH (SEQ ID NO:593); or HHHHHH (SEQ ID NO:594)). In some embodiments, the histidine tag is covalently linked (e.g, via a peptide bond) to the N-terminus or C- terminus of the peptide having a sequence at least 93% identical (e.g., 93% or 100% identical) to SEQ ID NO: 1 (ILWRQDIDLGVSREV). In some embodiments, the histidine tag is covalently linked (e.g., via a peptide bond) to the N-terminus or C-terminus of the peptide having a sequence at least 88% identical (e.g. 88.8% or 100% identical) to SEQ ID NO:2 (LDPETGEFL).

[0136] In some embodiments, the first polymer side chain group has a net positive charge. In some embodiments, the first polymer side chain group has a sequence 100% identical to any one of SEQ ID NOs:3 to 592 (see TABLE 1).

[0137] Alternatively, in some embodiments, the polymer can be a copolymer comprising (e.g., derived from) more than one type of monomer (e.g., from 2 to 10, 2 to 8, 2 to 6, 2 to 4, 4 to 10, 4 to 8, 4 to 6, 6 to 10, 6 to 8, or 8 to 10 types of monomers). In some embodiments, the polymer, along with the linked polymer side chains, can have any suitable configuration. For example, in some embodiments where the polymer is a homopolymer, the polymer can be a brush polymer. In other embodiments where the polymer is a copolymer, the polymer can be a brush block copolymer or brush random copolymer.

[0138] Thus, at least one polymer side chain (e.g., the first polymer segment) includes a therapeutic polypeptide. In some embodiments, the therapeutic polypeptide comprises any suitable number of amino acids so long as the peptide incorporates a sequence having at least 93% (e.g, 93.3% or 100%) sequence identity to SEQ ID NO: 1 (ILWRQDIDLGVSREV), or at least 88% (e.g., 88.8% or 100%) sequence identity to SEQ ID NO:2 (LDPETGEFL).

[0139] In some embodiments, the therapeutic peptide comprises 9 to 100 amino acids (e.g, 9 to 100, 10 to 100, 12 to 100, 14 to 100, 16 to 100, 18 to 100, 20 to 100, 30 to 100, 40 to 100, 50 to 100, 60 to 100, 70 to 100, 80 to 100, 90 to 100, 9 to 80, 10 to 80, 12 to 80, 14 to 80, 16 to 80, 18 to 80, 20 to 80, 30 to 80, 40 to 80, 50 to 80, 60 to 80, 70 to 80, 9 to 60, 10 to

60, 12 to 60, 14 to 60, 16 to 60, 18 to 60, 20 to 60, 30 to 60, 40 to 60, 50 to 60, 9 to 40, 10 to

40, 12 to 40, 14 to 40, 16 to 40, 18 to 40, 20 to 40, 30 to 40, 9 to 20, 10 to 20, 12 to 20, 14 to

20, 16 to 20, or 18 to 20 amino acids).

[0140] In some embodiments, the polypeptide can have any suitable structure (e.g., primary, secondary, tertiary, or quaternary structure) described herein. The polypeptide can be a branched polypeptide, a linear polypeptide, a cyclic polypeptide, or a cross-linked polypeptide. In some embodiments, the polymer is characterized by a structure where at least a portion of the polypeptide is linked to the polymer backbone group via an enzymatically degradable linker, such as a matrix metalloproteinase (MMP) cleavage sequence, a cathepsin B cleavage sequence, an ester bond, a reductive sensitive disulfide bond, a pH sensitive imine bond or any combinations of these. In other embodiments, the polymer is characterized by a structure wherein at least a portion of the polypeptide side-chain is linked to the polymer backbone or includes a degradable or triggerable linker. In some embodiments, the polypeptide and/or polymer further includes a tag for imaging and/or analysis. For example, the polypeptide and/or polymer can further include a dye, radiolabeling, an imaging agent, tritiation, and the like.

[0141] In some embodiments, a polymer of the present disclosure has the formula:

QkT-Q ² (Formula I);

Q -T-fSJh-Q ² (Formula II);

Q ¹ -[S]h-T-Q ² (Formula III);

Q ¹ -[S]i-T-[S]h-Q ² (Formula IV); Q ¹ -[S]i-T-[S]h-T-Q ² (Formula V);

Q ¹ -T-[S]i-T-[S]h-Q ² (Formula VI); or

Q ¹ -T-[S]i-T-[S]h-T-Q ² (Formula VII), wherein each T is independently the first polymer segment, each S is independently an additional polymer segment, Q ¹ is a first backbone terminating group and Q ² is a second backbone terminating group, h is zero or an integer selected over the range of 1 to 1000 (e.g., 1 to 1000, 1 to 750, 1 to 500, 1 to 250, 1 to 100, 1 to 50, 50 to 1000, 50 to 750, 50 to 500, 50 to 250, 50 to 100, 100 to 1000, 100 to 750, 100 to 500, 100 to 250, 250 to 1000, 250 to 750, 250 to 500, 500 to 1000, or 500 to 750), and i is zero or an integer selected over the range of 1 to 1000 (e.g., 1 to 1000, 1 to 750, 1 to 500, 1 to 250, 1 to 100, 1 to 50, 50 to 1000, 50 to 750, 50 to 500, 50 to 250, 50 to 100, 100 to 1000, 100 to 750, 100 to 500, 100 to 250, 250 to 1000, 250 to 750, 250 to 500, 500 to 1000, or 500 to 750).

[0142] In an embodiment, the polymer is characterized by any one of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or Formula VII, wherein each -T- is independently -[ Y^m-, wherein each Y ¹ is independently the first repeating unit of the first polymer segment, and each m is independently zero or an integer selected over the range of 1 to 1000 e.g., 1 to 1000, 1 to 750, 1 to 500, 1 to 250, 1 to 100, 1 to 50, 50 to 1000, 50 to 750, 50 to 500, 50 to 250, 50 to 100, 100 to 1000, 100 to 750, 100 to 500, 100 to 250, 250 to 1000, 250 to 750, 250 to 500, 500 to 1000, or 500 to 750), provided that at least one m is an integer selected over the range of 1 to 1000 (e.g., 1 to 1000, 1 to 750, 1 to 500, 1 to 250, 1 to 100, 1 to 50, 50 to 1000, 50 to 750, 50 to 500, 50 to 250, 50 to 100, 100 to 1000, 100 to 750, 100 to 500, 100 to 250, 250 to 1000, 250 to 750, 250 to 500, 500 to 1000, or 500 to 750). In some embodiments, each of the first polymer segment backbone group and/or the additional polymer segment backbone group is a substituted or unsubstituted polymerized norbomene, olefin, cyclic olefin, norbomene anhydride, cyclooctene, cyclopentadiene, styrene, acrylamide, or acrylate.

[0143] In some embodiments, a polymer of the present disclosure has the formula:

(Formula la); (Formula Ila); or (Formula Illa), wherein each Z ¹ is independently a first polymer backbone group and each Z ² is independently a second polymer backbone group, each S is independently a repeating unit different than the first repeating unit, Q ¹ is a first backbone termination group and Q ² is a second backbone termination group, each L ¹ is independently a first linking group and each L ² is independently a second linking group, each P ¹ is the peptide and each P ² is a polymer side chain different than the peptide, each m is independently an integer selected over the range of 2 to 1000 (e.g., 2 to 1000, 2 to 750, 2 to 500, 2 to 250, 2 to 100, 2 to 50, 50 to 1000, 50 to 750, 50 to 500, 50 to 250, 50 to 100, 100 to 1000, 100 to 750, 100 to 500, 100 to 250, 250 to 1000, 250 to 750, 250 to 500, 500 to 1000, or 500 to 750), each n is independently zero or an integer selected over the range of 1 to 1000 (e.g., 1 to 1000, 1 to 750, 1 to 500, 1 to 250, 1 to 100, 1 to 50, 50 to 1000, 50 to 750, 50 to 500, 50 to 250, 50 to 100, 100 to 1000, 100 to 750, 100 to 500, 100 to 250, 250 to 1000, 250 to 750, 250 to 500, 500 to 1000, or 500 to 750), and each h is independently zero or an integer selected over the range of 1 to 1000 (e.g., 1 to 1000, 1 to 750, 1 to 500, 1 to 250, 1 to 100, 1 to 50, 50 to 1000, 50 to 750, 50 to 500, 50 to 250, 50 to 100, 100 to 1000, 100 to 750, 100 to 500, 100 to 250, 250 to 1000, 250 to 750, 250 to 500, 500 to 1000, or 500 to 750). In some embodiments, each of the first polymer segment backbone group and/or the additional polymer segment backbone group is a substituted or unsubstituted polymerized norbornene, olefin, cyclic olefin, norbornene anhydride, cyclooctene, cyclopentadiene, styrene, acrylamide, or acrylate. In some embodiments, the first polymer segment backbone group and/or the additional polymer segment backbone group is N-(hexanoic acid)-c/.s-5-norbornene-c.w-2,3-dicarboximide.

[0144] For each of the polymers characterized by Formula la, Formula Ila, or Formula Illa, described herein, it will be understood that the first polymer backbone group units, the second polymer backbone group units, and the repeating unit having a composition different from the first repeating unit can be arranged in any suitable order. For example, the first polymer backbone group units, the second polymer backbone group units, and the repeating unit having a composition different from the first repeating unit can be arranged as a random polymer, block polymer, brush, brush block, alternating, segmented, grafted, tapered or other architectures. In other words, variables “m,” “n,” and “h” merely define the total number of that particular monomer in the polymer and do not imply any particular order.

[0145] In certain embodiments, for each of the polymers characterized by Formula la, Formula Ila, or Formula Illa, each of Z ¹ and Z ² can be any suitable monomer capable of undergoing ring opening metathesis or cross metathesis. For example, each of Z ¹ and Z ² can independently be a substituted or unsubstituted norbornene, oxanorbomene, olefin, cyclic olefin, cyclooctene, or cyclopentadiene. In some embodiments, each of the first polymer backbone group and/or the second polymer backbone group is a polymerized norbomene dicarboxyimide monomer. In some embodiments, each polymer backbone group of the polymer is a polymerized norbornene di carboxyimide monomer.

[0146] Thus, for each of the polymers characterized by Formula la, Formula Ila, or Formula Illa, each Z ¹ connected to L ¹ , and P ¹ or a combination thereof can independently be characterized by Formula VIII or Formula IX: (Formula IX). and when present, each Z ² connected to L ² , and P ² or a combination thereof can independently be characterized by Formula X or (Formula XI):

(Formula XI).

[0147] In certain embodiments of the polymers characterized by Formula la, Formula Ila, or Formula Illa, each Z ¹ connected to L ¹ , and P ¹ or a combination thereof is independently characterized by Formula VIII and/or each Z ² connected to L ² , and P ² or a combination thereof is independently characterized by Formula X.

[0148] For each of the polymers characterized by Formula I; Formula II; Formula III; Formula IV; Formula V; Formula VI; Formula VII, Formula la, Formula Ila, or Formula Illa, each of Q ¹ and Q ² can independently be selected from a hydrogen, C1-C30 alkyl, C3-C30 cycloalkyl, C5-C30 aryl, C5- C30 heteroaryl, C1-C30 acyl, C1-C30 hydroxyl, C1-C30 alkoxy, C2- C30 alkenyl, C2-C30 alkynyl, C ₅ -C ₃ oalkylaryl, — CO2R ³ , — CONR ⁴ R ⁵ , —COR ⁶ , — SOR ⁷ , — OSR ⁸ , — SO2R ⁹ , —OR ¹⁰ , — SR ¹¹ , — NR ¹² R ¹³ , — NR ¹⁴ COR ¹⁵ , C1-C30 alkyl halide, phosphonate, phosphonic acid, silane, siloxane, silsesqui oxane, C2-C30 halocarbon chain, C2- C30 perfluorocarbon, C2-C30 polyethylene glycol, metal, or metal complex, wherein each of R ³ -R ¹⁵ is independently H, C5-C10 aryl or Ci- C10 alkyl.

[0149] For each of the polymers characterized by Formula la, Formula Ila, or Formula Illa, each of L ¹ and L ² can be any suitable linking group. For example, each of L ¹ and L ² can independently be selected from a single bond, an oxygen, and groups having an alkyl group, an alkenylene group, an arylene group, an alkoxy group, an acyl group, a triazole group, a diazole group, a pyrazole group, and combinations thereof. In certain embodiments, each of L ¹ and L ² is independently selected from a single bond, — O — , C1-C10 alkyl, C2- C10 alkenylene, C3- C10 arylene, Ci- C10 alkoxy, Ci- C10 acyl and combinations thereof.

[0150] For each of the polymers characterized by Formula la, Formula Ila, or Formula Illa, each P ² is a polymer side chain having a composition different from that of P ¹ . Thus, P ² can be any suitable side chain capable of being incorporated into the polymer with P ¹ . In some embodiments, P ² is a peptide or protein other than P ¹ . Thus, a polymer of the present disclosure can comprise two different peptide or protein units. In some embodiments, P ² is a nonionic polymer selected from a polyalkylene glycol, a polyetheramine, a polyethylene oxide/polypropylene oxide copolymer, a polysaccharide, and combinations thereof. In certain embodiments, the nonionic polymer is a polyalkylene glycol e.g., polyethylene glycol (PEG) or polypropylene oxide (PPO)), a polyethylene oxide/polypropylene oxide copolymer, or a combination thereof. In some embodiments, the nonionic polymer is a polyethylene glycol (PEG). Thus, in some embodiments, each Z ² connected to L ² , and P ² or a combination thereof independently has the formula: (Formula XIII), wherein q is an integer from 1 to 500 (e.g., 1 to 500, 1 to 250, 1 to 100, 1 to 50, 1 to 25, 1 to

10, 1 to 6, 6 to 500, 6 to 250, 6 to 100, 6 to 50, 6 to 25, 6 to 10, 10 to 500, 10 to 250, 10 to

100, 10 to 50, 10 to 25, 25 to 500, 25 to 250, 25 to 100, 25 to 50, 50 to 500, 50 to 250, 50 to 100, 100 to 500, 100 to 250, or 250 to 500).

[0151] For each of the polymers characterized by Formula la, Formula Ila, or Formula

IIIA, each S is independently a repeating unit having a composition different from the first repeating unit. Thus, S can be any monomer unit capable of being incorporated into the polymer with P ¹ . In some embodiments, S comprises a nonionic polymer selected from a polyalkylene glycol, a polyetheramine, a polyethylene oxide/polypropylene oxide copolymer, a polysaccharide, and combinations thereof. In some embodiments, the nonionic polymer is a polyalkylene glycol (e.g., polyethylene glycol (PEG) or polypropylene oxide (PPO)), a polyethylene oxide/polypropylene oxide copolymer, or a combination thereof. In some embodiments, the nonionic polymer is a polyethylene glycol (PEG). In some embodiments, each S is independently characterized by Formula XII or Formula XIII, wherein q is an integer from 1 to 500 (e.g., 1 to 500, 1 to 250, 1 to 100, 1 to 50, 1 to 25, 1 to 10, 1 to 6, 6 to 500, 6 to 250, 6 to 100, 6 to 50, 6 to 25, 6 to 10, 10 to 500, 10 to 250, 10 to 100, 10 to 50, 10 to 25, 25 to 500, 25 to 250, 25 to 100, 25 to 50, 50 to 500, 50 to 250, 50 to 100, 100 to 500, 100 to 250, or 250 to 500).

[0152] In certain embodiments, a polymer of the present disclosure is characterized as having Formula la, Formula Ila, or Formula Illa, wherein each Z ¹ is independently a first polymer backbone group and each Z ² is independently a second polymer backbone group, each S is independently a repeating unit different than the first repeating unit, Q ¹ is a first backbone termination group and Q ² is a second backbone termination group, each L ¹ is independently a first linking group and each L ² is independently a second linking group, each P ¹ is the polymer side chain comprising the peptide and each P ² is a polymer side chain having a composition different from that of P ¹ , each m is independently an integer selected over the range of 2 to 100 (e.g., 2 to 100, 2 to 75, 2 to 50, 2 to 25, 2 to 10, 2 to 5, 5 to 100, 5 to 75, 5 to 50, 5 to 25, 5 to 10, 10 to 100, 10 to 75, 10 to 50, 10 to 25, 25 to 100, 25 to 75, 25 to 50, 50 to 100, or 50 to 75), each n is independently zero or an integer selected over the range of 1 to 100 (e.g., 1 to 100, 1 to 75, 1 to 50, 1 to 25, 1 to 10, 1 to 5, 5 to 100, 5 to 75, 5 to 50, 5 to 25, 5 to 10, 10 to 100, 10 to 75, 10 to 50, 10 to 25, 25 to 100, 25 to 75, 25 to 50, 50 to 100, or 50 to 75), and each h is independently zero or an integer selected over the range of 1 to 100 (e.g., 1 to 100, 1 to 75, 1 to 50, 1 to 25, 1 to 10, 1 to 5, 5 to 100, 5 to 75, 5 to 50, 5 to 25, 5 to 10, 10 to 100, 10 to 75, 10 to 50, 10 to 25, 25 to 100, 25 to 75, 25 to 50, 50 to 100, or 50 to 75), provided that each of the first polymer backbone group and/or the second polymer backbone group is a polymerized norbornene di carboxyimide monomer, and wherein the peptide comprises a sequence having at least 93% (e.g., 93.3% or 100%) sequence identity to SEQ ID NO: 1 (ILWRQDIDLGVSREV) or at least 98% (e.g., 98.8% or 100% sequence identity to SEQ ID NO:2 (LDPETGEFL). In some embodiments, the first polymer segment backbone group and/or the additional polymer segment backbone group is N-(hexanoic acid)- cz -5-norbomene-exo-2,3-dicarboximide.

[0153] In some embodiments, the polymer further fulfills (i) and/or (ii) of the following properties:

(i) the polymer has a degree of polymerization of 5 to 100 (e.g., 5 to 100, 10 to 100, 15 to 100, 20 to 100, 25 to 100, 30 to 100, 50 to 100, 60 to 100, 70 to 100, 80 to 100, 90 to 100, 5 to 80, 10 to 80, 15 to 80, 20 to 80, 25 to 80, 30 to 80, 50 to 80, 60 to 80, 70 to 80, 5 to 60, 10 to 60, 15 to 60, 20 to 60, 25 to 60, 30 to 60, 50 to 60, 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 5 to 25, 10 to 25, 15 to 25, 20 to 25, or 5 to 10), and (ii) the polymer has a peptide density of greater than 50% (e.g., greater than 50%, greater than 60%, greater than 70%, greater than 80%, or greater than 90%), as defined by the following formula:

In some embodiments, the polymer fulfills both of properties (i) and (ii) above.

[0154] In some embodiments, the polymer comprises one or more peptides and/or proteins other than the Nrf2-derived peptide described herein (i.e. one or more additional peptides and/or proteins). For example, each polymer segment S of Formula I; Formula II; Formula III; Formula IV; Formula V; Formula VI; or Formula VII can independently include a peptide or protein other than the Nrf2-derived peptide described herein. Similarly, each P ² of formula (Formula la), (Formula Ila), or (Formula Illa), can independently comprise a peptide or protein other than the Nrf2-derived peptide described herein.

[0155] The one or more additional peptides and/or proteins can be any suitable peptide or protein, having any suitable function. For example, the one or more additional peptides and/or proteins can be an additional therapeutic peptide (e.g., an additional therapeutic peptide described herein), a cell-penetrating agent (e.g., a cell-penetrating peptide), a targeting agent (e.g., a target specific peptide to a tissue or cell type), a therapeutically synergistic disease-specific peptide (e.g., a peptide known or thought to be therapeutic for a disease state, such as but not limited to, neurodegenerative disease), an antibody, or a combination thereof. The additional peptides and/or proteins can be linked to the polymer backbone by any suitable means. In some embodiments, the additional peptides and/or proteins are linked to the polymer backbone via an enzymatically degradable linker (i.e. a linking group or linking moiety). Examples of suitable cleavable, degradable or triggerable linkers include enzyme cleavable sequences such as one or more matrix metalloproteinase (MMP) cleavage sequence, cathepsin B cleavage sequence, ester bond, reductive sensitive disulfide bond, and pH sensitive imine bond, among others.

[0156] The one or more additional peptides and/or proteins can have any suitable number of amino acids. For example, the one or more additional peptides and/or proteins can include 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, or 30 or more amino acids. Alternatively, or in addition, the one or more additional peptides and/or proteins can have 100 or less amino acids, for example, 90 or less, 80 or less, 70 or less, 60 or less, 59 or less, 58 or less, 57 or less, 56 or less, 55 or less, 54 or less, 53 or less, 52 or less, 51 or less, 50 or less, 49 or less, 48 or less, 47 or less, 46 or less, 45 or less, 44 or less, 43 or less, 42 or less, 41 or less, 40 or less, 39 or less, 38 or less, 37 or less, 36 or less, 35 or less, 34 or less, 33 or less, 32 or less, or 31 or less amino acids. Thus, the one or more additional peptides and/or proteins can include a number of amino acids bounded by any two of the aforementioned endpoints. For example, the one or more additional peptides and/or proteins can have 2 to 100 amino acids, for example, 2 to 100, 4 to 100, 6 to 100, 8 to 100, 10 to 100, 15 to 100, 20 to 100, 25 to 100, 30 to 100, 40 to 100, 50 to 100, 60 to 100, 70 to 100, 80 to 100, 90 to 100, 2 to 80, 4 to 80, 6 to 80, 8 to 80, 10 to 80, 15 to 80, 20 to 80, 25 to 80, 30 to 80, 40 to 80, 50 to 80, 60 to 80, 70 to 80, 2 to 60, 4 to 60, 6 to 60, 8 to 60, 10 to 60, 15 to 60, 20 to 60, 25 to 60, 30 to 60, 40 to 60, 50 to 60, 2 to 40, 4 to 40, 6 to 40, 8 to 40, 10 to 40, 15 to 40, 20 to 40, 25 to 40, 30 to 40, 2 to 20, 4 to 20, 6 to 20, 8 to 20, 10 to 20, 15 to 20, 2 to 10, 4 to 10, 6 to 10, or 8 to 10 amino acids. In some embodiments, the one or more additional peptides and/or proteins is composed of 5 to 100 amino acids. In some embodiments, the one or more additional peptides and/or proteins is composed of 8 to 60 amino acid.

[0157] The one or more additional peptides and/or proteins can have any suitable structure (e.g., primary, secondary, tertiary, or quaternary structure). Additionally, the one or more additional peptides and/or proteins can be branched, linear, cyclic, or cross-linked. In some embodiments, the one or more additional peptides and/or proteins is a charge modulating domain. For example, the one or more additional peptides and/or proteins can be or can comprise a TAT sequence, a glycine-serine domain, a cationic residue domain, or a combination thereof, or optionally a glycine-serine domain, a cationic residue domain, or a combination thereof. In certain embodiments, the one or more additional peptides and/or proteins modulates the charge of the polymer to have a net positive charge. Without wishing to be bound by any particular theory, it is believed that the net positive charge increases the cellular uptake of the polymer comprising the peptide.

[0158] In some embodiments, a polymer of the present disclosure incorporates a tag for imaging and/or analysis. For example, each polymer segment S of Formula I; Formula II; Formula III; Formula IV; Formula V; Formula VI; or Formula VII can independently include a tag for imaging and/or analysis. Similarly, each P ² of Formula la, Formula Ila, or Formula Illa can independently incorporate a tag for imaging and/or analysis. For example, the polymer can incorporate a dye, a radiolabel, an imaging agent, tritiation, and the like. [0159] After polymerization, polymers disclosed herein may be characterized using any suitable technique(s). For example, polymers can be characterized by size-exclusion chromatography with multiangle light scattering (SEC-MALS), sometimes referred to as gel permeation chromatography (GPC), to ascertain degree of polymerization (DP) and molecular weight distribution (dispersity or Mw/Mn). Alternatively, or in addition to, polymers can be characterized by SDS-PAGE to ascertain degree of polymerization (DP) and molecular weight. In some embodiments, there is suitable agreement between the obtained DP and the theoretical DP based on the initial monomer-to-initiator ratio ([M]o/[I]o).

[0160] Polymers of the present disclosure can have any suitable degree of polymerization. Without being bound to any particular theory, if the degree of polymerization is too low, the polymer may not be resistant to enzymatic cleavage by proteases or may be cleared too rapidly from the body since the polymer’s molecular weight would be lower than the clearance threshold through the kidney. Alternatively, without being bound to any particular theory, if the degree of polymerization is too high, the peptide side chain groups displayed on the polymer may be too dense to engage their biological targets (e.g., Keapl). Typically, the polymer has a degree of polymerization of 2 to 1000 (e.g., 2 to 5, 2 to 10, 2 to 15, 2 to 20, 2 to 25, 2 to 30, 2 to 40, 2 to 50, 2 to 75, 2 to 100, 2 to 150, 2 to 200, 2 to 250, 2 to 500, 2 to 750, 2 to 1000, 5 to 10, 5 to 15, 5 to 20, 5 to 25, 5 to 30, 5 to 40, 5 to 50, 5 to 75, 5 to 100, 5 to 150, 5 to 200, 5 to 250, 5 to 500, 5 to 750, 5 to 1000, 10 to 15, 10 to 20, 10 to 25, 10 to 30, 10 to 40, 10 to 50, 10 to 75, 10 to 100, 10 to 150, 10 to 200, 10 to 250, 10 to 500, 10 to 750, 10 to 1000, 20 to 25, 20 to 30, 20 to 40, 20 to 50, 20 to 75, 20 to 100, 20 to 150, 20 to 200, 20 to 250, 20 to 500, 20 to 750, 20 to 1000, 30 to 40, 30 to 50, 30 to 75, 30 to 100, 30 to 150, 30 to 200, 30 to 250, 30 to 500, 30 to 750, 30 to 1000, 50 to 75, 50 to 100, 50 to 150, 50 to 200, 50 to 250, 50 to 500, 50 to 750, 50 to 1000, 100 to 150, 100 to 200, 100 to 250, 100 to 500, 100 to 750, 100 to 1000, 250 to 500, 250 to 750, 250 to 1000, 500 to 750, or 500 to 1000). In certain embodiments, the polymer has a degree of polymerization of 5 to 100. In some embodiments, the polymer has a degree of polymerization of 5 to 50. For example, the polymer can have a degree of polymerization of 5 or about 5, a degree of polymerization of 15 or about 15 (e.g., 17), a degree of polymerization of 30 or about 30, or a degree of polymerization of 50 or about 50. In certain embodiments, the polymer has a degree of polymerization of at least 20. Without wishing to be bound by any particular theory, it is believed that a degree of polymerization of at least 20 allows for the protein-like polymer to bridge the gap between both Kelch domains of a Keapl homodimer, thereby increasing binding interactions by stably binding both Kelch domains simultaneously. [0161] In some embodiments, polymers of the present disclosure can have any suitable average molecular weight. In some embodiments, polymers of the present disclosure can have an average molecular weight of 2,000 kDa or less, for example, 1,800 kDa or less, 1,600 kDa or less, 1,400 kDa or less, 1,200 kDa or less, 1,000 kDa or less, 900 kDa, or less, 800 kDa, or less, 700 kDa or less, 600 kDa or less, 500 kDa or less, 250 kDa or less, 100 kDa or less, or 50 kDa or less. Alternatively, or in addition, polymers of the present disclosure can have an average molecular weight of 500 Da or more, for example, 1 kDa or more, 5 kDa or more, or 10 kDa or more. In some embodiments, polymers of the present disclosure can have an average molecular weight bounded by any two of the aforementioned endpoints. For example, the polymers can have an average molecular weight of from 500 Da to 2,000 kDa, from 500 Da to 1,000 kDa, from 500 Da to 500 kDa, from 500 Da to 100 kDa, from 500 Da to 50 kDa, 1 kDa to 2,000 kDa, from 1 kDa to 1,000 kDa, from 1 kDa to 500 kDa, from 1 kDa to 100 kDa, from 1 kDa to 50 kDa, 5 kDa to 2,000 kDa, from 5 kDa to 1,000 kDa, from 5 kDa to 500 kDa, from 5 kDa to 100 kDa, from 5 kDa to 50 kDa, 10 kDa to 2,000 kDa, from 10 kDa to 1,000 kDa, from 10 kDa to 500 kDa, from 10 kDa to 100 kDa, or from 10 kDa to 50 kDa.

[0162] Generally, the polymers described herein are characterized by a brush density of greater than or equal to 50% (e.g., greater than or equal to 55%, greater than or equal to 60%, greater than or equal to 65%, greater than or equal to 70%, greater than or equal to 75%, greater than or equal to 80%, greater than or equal to 85%, greater than or equal to 90%, or greater than or equal to 95%). For example, in some embodiments polymers of the present disclosure have a brush density greater than or equal to 70%. In some embodiments, polymers of the present disclosure have a brush density greater than or equal to 90%. In some embodiments, brush polymers of some embodiments are characterized by a brush density selected from the range of 50% to 100% e.g., 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 50% to 90%, 60% to 90%, 70% to 90%, 80% to 90%, 50% to 80%, 60% to 80%, 70% to 80%, 50% to 70%, 60% to 70%, or 50% to 60%).

[0163] In some embodiments, polymers of the present disclosure can have any suitable peptide density. The polymer may be characterized by peptide density which refers to the percentage of the repeating units comprising a polymer backbone group covalently linked to at least one peptide. Thus, for each of the polymers characterized by the formula (Formula la), (Formula Ila), or (Formula Illa), the peptide density can be defined by the following formula: P ¹ x 100.

P + P ² + S

[0164] Generally, the polymers described herein are characterized by a peptide density of greater than or equal to 50% (e.g., greater than or equal to 55%, greater than or equal to 60%, greater than or equal to 65%, greater than or equal to 70%, greater than or equal to 75%, greater than or equal to 80%, greater than or equal to 85%, greater than or equal to 90%, or greater than or equal to 95%). For example, in some embodiments, polymers disclosed herein have a peptide density greater than or equal to 70%. In some embodiments, polymers of the present disclosure have a peptide density greater than or equal to 90%. In some embodiments, brush polymers of some embodiments are characterized by a peptide density selected from the range 50% to 100% (e.g, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 50% to 90%, 60% to 90%, 70% to 90%, 80% to 90%, 50% to 80%, 60% to 80%, 70% to 80%, 50% to 70%, 60% to 70%, or 50% to 60%). In some embodiments, the brush density is equivalent to the peptide density.

[0165] In another aspect, the disclosure provides a pharmaceutical composition comprising one or more peptides and/or one or more polymers described herein.

3. Pharmaceutical Compositions

[0166] Polypeptides and polymers described herein can be used in the manufacture of pharmaceutical compositions. In some embodiments, pharmaceutical compositions disclosed herein comprise polypeptides or polymers of the present disclosure and a pharmaceutically acceptable carrier and, optionally, other medicinal agents, pharmaceutical agents, stabilizing agents, buffers, carriers, adjuvants, diluents, etc. By “pharmaceutically acceptable” it is meant a material that is not toxic or otherwise undesirable, i.e., the material may be administered to a subject without causing any undesirable biological effects.

[0167] In some embodiments, pharmaceutical compositions described herein comprise one or more pharmaceutically acceptable excipients. For example, the peptides and/or polymers of the disclosure can be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. Alternatively, the peptides and/or polymers can be injected intra-tum orally. In some embodiments, formulations for injection will commonly comprise a solution of the peptide and/or polymer dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. In some embodiments, formulations can be sterilized by conventional, well known sterilization techniques known in the art. The formulations can contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the peptide and/or polymer in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. In certain embodiments, the concentration of a peptide and/or polymer in a solution formulation for injection will range from 0.1% (w/w) to 10% (w/w) (e.g., 0.1% to 10%, 0.5% to 10%, 1% to 10%, 1.5% to 10%, 2% to 10%, 2.5% to 10%, 3% to 10%, 3.5% to 10%, 4% to 10%, 4.5% to 10%, 5% to 10%, 5.5% to 10%, 6% to 10%, 6.5% to 10%, 7% to 10%, 7.5% to 10%, 8% to 10%, 8.5% to 10%, 9% to 10%, 9.5% to 10%, 0.1% to 8%, 0.5% to 8%, 1% to 8%, 1.5% to 8%, 2% to 8%, 2.5% to 8%, 3% to 8%, 3.5% to 8%, 4% to 8%, 4.5% to 8%, 5% to 8%, 5.5% to 8%, 6% to 8%, 6.5% to 8%, 7% to 8%, 7.5% to 8%, 0.1% to 6%, 0.5% to 6%, 1% to 6%, 1.5% to 6%, 2% to 6%, 2.5% to 6%, 3% to 6%, 3.5% to 6%, 4% to 6%, 4.5% to 6%, 5% to 6%, 5.5% to 6%, 0.1% to 4%, 0.5% to 4%, 1% to 4%, 1.5% to 4%, 2% to 4%, 2.5% to 4%, 3% to 4%, 3.5% to 4%, 0.1% to 2%, 0.5% to 2%, 1% to 2%, 1.5% to 2%, 0.1% to 1%, or 0.5% to 1%).

[0168] In some embodiments, pharmaceutical compositions can comprise sterile aqueous and non-aqueous injection solutions, which are optionally isotonic with the blood of the subject to whom the pharmaceutical composition is to be delivered. Pharmaceutical compositions can contain anti-oxidants, buffers, bacteriostats and solutes, which render the composition isotonic with the blood of the intended subject to be administered. Aqueous and non-aqueous sterile suspensions, solutions and emulsions can include suspending agents and thickening agents. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. In some embodiments pharmaceutical compositions comprise pharmaceutically acceptable vehicles and can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.

Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.

[0169] In some embodiments, pharmaceutical compositions disclosed herein further comprise an additional Keapl inhibitor orNrf2 inducer. For example the composition can further comprise an additional small molecule drug such as dimethyl fumarate, tertbutylhydroquinone, DL-sulforaphane, or the like. Other small molecule Keapl inhibitors or Nrf2 inducers will be readily apparent to those skill in the art. In some embodiments, the composition further comprises an additional Keapl inhibiting peptide. For example, in some embodiments, the composition can comprise a protein-like polymer described herein and an additional peptide.

[0170] The peptide, polymer, and/or pharmaceutical composition can be administered by oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. In some embodiments, the peptide, polymer, and/or pharmaceutical composition is administered intravenously, subcutaneously, intramuscularly, topically, orally, or a combination thereof.

4. Methods of Treatment

[0171] In another aspect, the disclosure provides a method of treating a condition comprising administering to a subject an effective amount of a peptide, polymer, and/or pharmaceutical composition described herein.

[0172] The methods described herein can comprise contacting a target tissue, target cell, and/or target receptor of the subject with the peptide and/or polymer, pharmaceutical composition thereof, or a metabolite or product thereof. In some embodiments, the peptides and/or polymers described herein pass through the cell membrane and contact an intracellular target. Without wishing to be bound by any particular theory, the peptide/polymer structures and charge modulating peptides described herein play an integral role in facilitating cell permeability. [0173] In some embodiments, the methods described herein interrupt the protein-protein interaction between Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and Kelch-like ECH Associating protein 1 (Keapl) (e.g., by inhibiting binding to the ETGE motif (SEQ ID NO: 613) of Nrf2). Without wishing to be bound by any particular theory, inhibiting Keapl/Nrf2 binding can enhance the antioxidant and anti-inflammatory response to provide beneficial effects in both the central nervous system (CNS) and outside the central nervous system. Thus, the methods described herein can be used to treat and/or manage a condition associated with an inflammatory state, increased oxidative stress, autoimmune pathophysiology, chemo- preventative measures, neurodegeneration, or a combination thereof.

[0174] Methods disclosed herein include administering a therapeutically effective amount of a peptide, polymer, and/or composition described herein to a subject in need thereof. For example, the methods can include administering the peptide, polymer, and/or composition to provide a dose of 10 ng/kg to 50 mg/kg to the subject (e.g. 10 ng/kg to 50 mg/kg, 50 ng/kg to 50 mg/kg, 100 ng/kg to 50 mg/kg, 500 ng/kg to 50 mg/kg, 1 pg/kg to 50 mg/kg, 5 pg/kg to 50 mg/kg, 10 pg/kg to 50 mg/kg, 50 pg/kg to 50 mg/kg, 100 pg/kg to 50 mg/kg, 500 pg/kg to 50 mg/kg, 1 mg/kg to 50 mg/kg, 5 mg/kg to 50 mg/kg, 10 mg/kg to 50 mg/kg, 10 ng/kg to 10 mg/kg, 50 ng/kg to 10 mg/kg, 100 ng/kg to 10 mg/kg, 500 ng/kg to 10 mg/kg, 1 pg/kg to 10 mg/kg, 5 pg/kg to 10 mg/kg, 10 pg/kg to 10 mg/kg, 50 pg/kg to 10 mg/kg, 100 pg/kg to 10 mg/kg, 500 pg/kg to 10 mg/kg, 1 mg/kg to 10 mg/kg, 5 mg/kg to 10 mg/kg, 10 ng/kg to 5 mg/kg, 50 ng/kg to 5 mg/kg, 100 ng/kg to 5 mg/kg, 500 ng/kg to 5 mg/kg, 1 pg/kg to 5 mg/kg, 5 pg/kg to 5 mg/kg, 10 pg/kg to 5 mg/kg, 50 pg/kg to 5 mg/kg, 100 pg/kg to 5 mg/kg, 500 pg/kg to 5 mg/kg, 1 mg/kg to 5 mg/kg, 10 ng/kg to 1 mg/kg, 50 ng/kg to 1 mg/kg, 100 ng/kg to 1 mg/kg, 500 ng/kg to 1 mg/kg, 1 pg/kg to 1 mg/kg, 5 pg/kg to 1 mg/kg, 10 pg/kg to 1 mg/kg, 50 pg/kg to 1 mg/kg, 100 pg/kg to 1 mg/kg, 500 pg/kg to 1 mg/kg, 10 ng/kg to 500 pg/kg, 50 ng/kg to 500 pg/kg, 100 ng/kg to 500 pg/kg, 500 ng/kg to 500 pg/kg, 1 pg/kg to 500 pg/kg, 5 pg/kg to 500 pg/kg, 10 pg/kg to 500 pg/kg, 50 pg/kg to 500 pg/kg, 100 pg/kg to 500 pg/kg, 500 pg/kg to 500 pg/kg, 1 mg/kg to 500 pg/kg, 5 mg/kg to 500 pg/kg, 10 mg/kg to 500 pg/kg, 10 ng/kg to 100 pg/kg, 50 ng/kg to 100 pg/kg, 100 ng/kg to 100 pg/kg, 500 ng/kg to 100 pg/kg, 1 pg/kg to 100 pg/kg, 5 pg/kg to 100 pg/kg, 10 pg/kg to 100 pg/kg, 50 pg/kg to 100 pg/kg, 10 ng/kg to 50 pg/kg, 50 ng/kg to 50 pg/kg, 100 ng/kg to 50 pg/kg, 500 ng/kg to 50 pg/kg, 1 pg/kg to 50 pg/kg, 5 pg/kg to 50 pg/kg, 10 pg/kg to 50 pg/kg, 10 ng/kg to 10 pg/kg, 50 ng/kg to 10 pg/kg, 100 ng/kg to 10 pg/kg, 500 ng/kg to 10 pg/kg, 1 pg/kg to 10 pg/kg, 5 pg/kg to 10 pg/kg, 10 ng/kg to 5 pg/kg, 50 ng/kg to 5 pg/kg, 100 ng/kg to 5 pg/kg, 500 ng/kg to 5 pg/kg, 1 pg/kg to 5 pg/kg, 10 ng/kg to 1 pg/kg, 50 ng/kg to 1 pg/kg, 100 ng/kg to 1 pg/kg, 500 ng/kg to 1 pg/kg, 10 ng/kg to 500 ng/kg, 50 ng/kg to 500 ng/kg, 100 ng/kg to 500 ng/kg, 10 ng/kg to 100 ng/kg, 50 ng/kg to 100 ng/kg, or 10 ng/kg to 50 ng/kg ). The peptide, polymer, or composition dose can also lie outside of these ranges, depending on the particular peptide, polymer, or composition as well as the type of disease being treated. Frequency of administration can range from a single dose to multiple doses per week, or more frequently. In some embodiments, the peptide, polymer, or composition is administered from about once per month to about five times per week. In some embodiments, the peptide and/or polymer is administered once per week.

[0175] In some embodiments, the methods described herein can be used to treat or manage an autoimmune disease. For example, the methods described herein can be used to treat or manage multiple sclerosis, systemic lupus erythematous, Sjogren syndrome, rheumatoid arthritis, vitiligo, psoriasis, or the like.

[0176] In some embodiments, the methods described herein can be used to treat or manage a respiratory disease. For example, the methods described herein can be used to treat or manage COPD, emphysema, potential treatment for smokers, idiopathic pulmonary fibrosis, chronic sarcoidosis, hypersensitivity pneumonitis, or the like.

[0177] In some embodiments, the methods described herein can be used to treat or manage a gastrointestinal disease. For example, the methods described herein can be used to treat or manage ulcerative colitis, ulcers, prevent acetaminophen toxicity, non-alcoholic steatohepatitis, primary biliary cholangitis, cirrhosis, type 2 diabetes, diabetic nephropathy, or the like.

[0178] In some embodiments, the methods described herein can be used to treat or manage a cardiovascular disease. For example, the methods described herein can be used to treat or manage cardiac ischemia-reperfusion injury, heart failure, atherosclerosis, or the like. [0179] In some embodiments, the methods described herein can be used to treat or manage a neurodegenerative disease. For example, the methods described herein can be used to treat or manage Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, Friedreich ataxia, frontotemporal lobar degeneration, or the like.

EXAMPLES

[0180] The disclosure now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure, and is not intended to limit the disclosure.

EXAMPLE 1: Enhanced Binding Efficiency of Polypeptide Sequences

[0181] This example shows the enhanced binding affinity of peptide sequences presently disclosed.

[0182] Keapl interacts with Nrf2 in a dimerized structure, wherein the DLG and ETGE (SEQ ID NO: 613) regions of Nrf2 bind two identical Kelch domains. To determine the degree of polymerization necessary for a polynorbomene dicarboxyimide-based PLP of the present disclosure to bind and bridge both Kelch domains of a Keapl homodimer simultaneously, MARTINI coarse-grained simulations is carried out using two Kelch domains, spaced 80 A apart to represent the natural structure of the Keap-1 homodimer.

[0183] A polymer or polypeptide comprising SEQ ID NO: 1, SEQ ID NO:2, or any sequence of Table 1 is evaluated using in silico experiments with AutoDock Vina software, which is capable of docking simulation as well as binding energy predictions. The binding affinities are calculated for binding of Keapl.

[0184] Similarly, a polymer or polypeptide comprising SEQ ID NO: 1, SEQ ID NO:2, or any sequence of Table 1, is evaluated using in silico simulations with CABS-Dock software, which is capable of simultaneous prediction of binding sites and protein-peptide docking through coarse-gain methods.

[0185] A polymer or polypeptide comprising SEQ ID NO: 1, SEQ ID NO:2, or any sequence of Table 1, is also evaluated using classical All-Atom MD simulations performed with GROMACS 2016.3. Lennard-Jones interactions and Coulombic interactions are monitored for 200s. Binding specificity calculations and modeling are also performed using Alphafold-multimer 2.1.1.

[0186] MARTINI coarse-grained simulations are additionally generated from the All-Atom structures using martinize.py downloaded at http://cgmartini.nl/. The structures are solvated in water separately and sodium chloride salt (0.15 M) is added. Energy minimization is first performed on the initial structure for 500 steps with the steepest descent algorithm.

Subsequently, 4 equilibration runs are carried out to fully equilibrate the system with the same MD integrator, V-rescale thermostat, and Berendsen barostat but different time steps (10 fs, 15 fs, 15 fs, and 15 fs) and position restraint force constants on the protein backbone (1000, 1000, 100, 10). Finally, each production run is performed for 3 ps with a time step of 15 fs. V-rescale thermostat and Parrinello-Rahman barostat are used to preserve temperature and pressure.

[0187] MARTINI binding energies for the complex between the Kelch domain and a polynorbornene dicarboxyimide-based protein-like polymer (PLP) of the present disclosure are also determined.

[0188] MARTINI coarse-grained simulations are carried out for polynorbornene dicarboxyimide-based PLPs of the present disclosure and the eighth peptide on the PLP backbone are aligned with the All-Atom simulation structures to ensure that the PLPs are initially docked into the Kelch binding pocket. Each production run is performed for 3 ps with a time step of 15 fs.

[0189] Similarly, MARTINI coarse-grained simulations are carried out for polynorbomene dicarboxyimide-based PLPs of the present disclosure, having a degree of polymerization of 5, 10, or 15. The middle peptide on the PLP backbone is aligned with the All-Atom simulation structures to ensure that the PLPs are initially docked into the Kelch binding pocket. Each production run is performed for 3 ps with a time step of 15 fs.

[0190] To further probe the binding between the Keapl Kelch domain and polypeptides of the present disclosure, in silico modeling between a Keapl dimer and polynorbomene dicarboxyimide-based PLPs of the present disclosure is performed.

EXAMPLE 2: Synthesis of a polynorbornene dicarboxyimide-based brush polymer

[0191] This example provides an exemplary synthesis of a polynorbomene dicarboxyimide-based brush polymer comprising a peptide having the sequence of SEQ ID NO: 1, SEQ ID NO:2, or any sequence of Table 1.

[0192] Peptides are synthesized using standard solid phase peptide synthesis (SPPS) procedures on an DCEM Liberty Blue automated synthesizer. The peptides are prepared on Rink amide MBHA resin with a typical SPPS procedure involving FMOC deprotection with 20% methylpiperidine in DMF (one 5 min deprotection followed by one 15 min deprotection), and 45 min. amide couplings using 3.75 eq. of the FMOC-protected, and side chain-protected amino acid, 4 eq. of HBTU and 8 eq. of DIPEA.

[0193] Peptide monomers are prepared by amide coupling to N-(hexanoic acid)-cA-5- norbomene-exo-2,3-dicarboximide at the N-terminus of the peptide. Following completion of the synthesis, the peptide or peptide monomer are cleaved from the resin by treatment with TFA/H2O/TIPS in a 9.5:2.5:2.5 ratio for 2 to 4 hours. The peptide or monomer are then filtered, precipitated and centrifuged in cold ether and dried overnight under vacuum. Cleaved monomers and peptides are characterized via analytical HPLC and mass spectrometry and then purified by RP-HPLC. The identity of the peptide monomer is confirmed by ESI-MS or MALDI-ToF MS and purity is verified by observation of a single peak in an analytical RP-HPLC chromatogram.

[0194] The purity of the peptide monomer is verified by scale RP-HPLC, where a single peak in the chromatogram of a newly purified peptide monomer indicates a pure material. RP-HPLC is performed on a Jupiter Proteo90A Phenomenex™ column (150 x 4.60 mm) equipped with a Hitachi -Elite™ LaChrom L2130 pump and a UV-Vis detector (Hitachi- Elite™ 10 LaChrom L-2420) monitoring at 214 nm. The peptide monomer is purified on a preparative scale Jupiter Proteo90A Phenomenex™ column (2050 x 25.0 mm) using an Armen Spot Prep II™ System and analyzed for purity using a gradient buffer system in which Buffer A is 0.1% TFA in water and Buffer B is 0.1% TFA in acetonitrile.

[0195] The identity of the peptide is confirmed by electrospray ionization (ESI) mass spectrometry.

[0196] Polymerizations are carried out in a glovebox under N2 by mixing the monomer and ROMP catalyst (e.g., Grubbs, Hovey da-Grubbs, or Schrock) in respective ratio (e.g., 5: 1, 10: 1, or 15: 1) in dry DMF to generate a polymer with desired degree of polymerization. For example, a DP of 10 involves mixing the monomer (0.0125 mmol, 10 equiv, 25 mM) with the ROMP catalyst (e.g., Grubbs, Hovey da-Grubbs, or Schrock) (0.00125 mmol, 1 equiv, 2.5 mM) in dry DMF (0.5 mL).

[0197] The polymerization reaction is monitored using 'H NMR spectroscopy by measuring the consumption of the peptide monomer and to determine the time period required to reach completion. Termination is performed with ethyl vinyl ether (10 eq.) for 30 minutes at room temperature with stirring. The resulting polymer is directly characterized by size exclusion chromatography coupled with multiangle light scattering (SEC-MALS). The polymer is precipitated with cold ether and collected by centrifugation and dried overnight. The protein-like-polymers (PLPs) are further purified using dialysis in regenerated cellulose (3500 Da pore size) and 2 liters of milliQ water over a 48 hour period. The water is renewed at 24 hours and at 48 hours the dialyzed materials are collected, sterile filtered using a 0.22 pm PES filter, and lyophilized.

[0198] Polymer dispersities (Mw/Mn) and molecular weights (Mn) are determined by SEC- MALS. SEC is performed on a Phenomenex Phenogel ™ 5u 10, 1K-75K, 300x7.80 mm column in series with a Phenomenex Phenogel™ 5u 10, 10K-1000K, 300x7.80 mm column, which runs with 0.05 M LiBr in DMF as the running buffer (flow rate of 0.75 mL/min) using a Shimadzu pump. The instrument is also equipped with a MAES detector (DAWN™ HELEOS™, Wyatt Technology) and a refractive index (RI) detector (Wyatt Optilab T-rEX detector). The entire SEC-MALS setup is normalized to a 30K MW polystyrene standard as determined by size-exclusion chromatography (SEC-MALS) coupled with multiangle light scattering, for the 5mer, lOmer, and 15mer (approximate) of the polynorbomene dicarboxyimide-based brush polymer, as prepared in this example.

[0199] The 5mer, lOmer, and 15mer (approximate) of the polynorbornene dicarboxyimide- based brush polymers are analyzed using SDS-polyacrylamide gel electrophoresis (PAGE). Samples are prepared for SDS-PAGE in milliQ water at a concentration of Img/ml, and are added to Laemmli sample buffer at a 2:3 ratio (20 pL buffer: 30 pL prepared sample) and then heated at 90 °C for 5 minutes. The resulting samples are loaded at 30 pL/well into an AnyKD mini Protean TGX™ Precast Protein Gel along with 10 pL of the Precision Plus Protein Dual Xtra 2-250kDa ladder. The gel is run in Tris/Gly/SDS Buffer at 120V until the samples reach the bottom of the gel. PLPs are visualized on the gel using an Instant Coomassie Blue Stain which is applied with shaking at 70 rpm for approximately 15 minutes. Gels are rinsed and imaged for further analysis.

EXAMPLE 3: Three-Dimensional Structures of Polynorbornene dicarboxymide-based brush polymers

[0200] This example provides an analysis of the three-dimensional structures exhibited by a low degree of polymerization polynorbornene dicarboxyimide-based brush polymer, a high degree of polymerization polynorbornene dicarboxyimide-based brush polymer, a partial scramble sequence polynorbomene dicarboxyimide-based brush polymer, and a full scramble sequence polynorbomene dicarboxyimide-based brush polymer.

[0201] SAXS experiments are conducted at the 5-ID-D beamline of the Dupont- Northwestem-Dow Collaborative Access Team (DND-CAT) at the Advanced Photon Source, 25 Argonne National Laboratory. PLPs are prepared in milliQ water at 5 mg/mL and loaded into 1.5 mm quartz capillaries for SAXS. The capillaries are sealed with epoxy to prevent solvent evaporation prior to data acquisition. Capillaries are loaded into a variable temperature multi-capillary holder. Two-dimensional scattering patterns are obtained from 10 second exposure using a Rayonix MX170-HS CCD area detector using a 0.5 second exposure time to X30 rays with a wavelength of = 0.7293 A and a sample-to-detector distance of 8.5 m. The 2D data are azimuthally averaged to yield ID scattering patterns as intensity versus q. Incoherent background scattering is measured by acquiring scattering patterns for a solvent- loaded capillary in the absence of polymer. The experimental data is fit to a power law of the form:

[0202] I(q) = A + Bc/' ^m + Ct/ ² , and subtracted from the polymer data, where 2 < m < 4. To more closely analyze high q scattering and gain further insight into polymer structure in solution, Kratky plots are constructed. Standard Kratky format, q ² I vs. q, are made dimensionless by multiplying q by Rg to normalize for different coil sizes and by dividing I by I(q = 0) to normalize for different molar masses and concentrations. This allows for direct comparison of the topology of the different PLPs, regardless of size and concentration, and observation of trends related to chemistry. A fully collapsed, spherical globule will show a bell-shaped profile in the Kratky format. The local maxima for a sphere occurs at qRg = 3 ^1/2 with I/ = 1.104. Peaks shifted to higher qRg and higher are more asymmetric and/or partially unfolded Gaussian coils plateau at I/ = , while fully extended chains will asymptotically increase.

[0203] To further analyze the probability distribution of mass in space the PLPs, pair distance distribution functions (PDDFs) are plotted. The pair distance distribution functions are generated by taking the inverse Fourier transform of scattering data to translate reciprocal space data into real space. The analysis is performed using the Ag’s determined by Guinier analysis and the gnom algorithm in ATSAS.

[0204] Using the dammif algorithm in the ATSAS software, a real space and coarsegrained image of the PLPs in solution are generated.

EXAMPLE 4: Structural Effects of PLPs Having Different Peptides and Polymer Backbones

[0205] This example shows the structural effects exhibited by a protein-like polymer (PLP) having (a) a structurally different peptide bound and (b) a structurally different polymer [0206] backbone, as determined by circular dichroism (CD).

[0207] The circular dichroism (CD) is taken for (a) polynorbomene dicarboxyimide monomers disclosed herein comprising a sequence of SEQ ID NO: 1, SEQ ID NO:2, or any sequence of Table 1, (b) a low degree of polymerization polynorbornene dicarboxyimide- based brush polymer, (c) a high degree of polymerization polynorbomene dicarboxyimide- based brush polymer, (d) a partial scrambled sequence polynorbornene di carboxyimide-based brush polymer, and (e) a full scrambled sequence polynorbornene dicarboxyimide-based brush polymer.

[0208] To demonstrate that the polymer backbone does not affect the secondary structures within the PLP, the circular dichroism (CD) is taken for (a) a low degree of polymerization polynorbornene dicarboxyimide-based brush polymer, (b) a high degree of polymerization polynorbornene dicarboxyimide-based brush polymer, (c) a low degree of polymerization (meth)acrylamide-based brush polymer, (d) a high degree of polymerization (meth)acrylamide-based brush polymer.

EXAMPLE 5: Binding affinities of Polypeptides and Protein-Like-Poly mers Determined by Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET)

[0209] This example provides the binding affinity exhibited by polypeptides, polynorbornene dicarboxyimide-based polymers of the present disclosure, as determined by time-resolved fluorescence energy transfer (TR-FRET).

[0210] The TR-FRET assay was performed by standard techniques as understood by persons skilled in the art and as described in Colarusso et al., 2020. Bioorg. Med. Chem.2 , 115738, and Bresciani et al., 2017. Arch. Biochem. Biophys. 631, 31-41. In brief, compounds (peptides or PLPs) were dissolved in water and transferred to the bottom of a white 384-well plate (Corning, USA) in a final volume of 10 pL. 10 nM biotinylated Kelch domain (bioKelch) was pre-incubated with 4 nM europium -labelled streptavidin (PerkinElmer, USA) in assay buffer (10 mM HEPES pH 7.4, 50 mM EDTA, 150 mM NaCl and 0.005% Tween™- 20), then 5 pL was added to compounds and incubated for 10 min at room temperature. Following incubation, 5 pL of 20 nM AF647-labeled 9-mer ETGE peptide in assay buffer was added to the reaction, incubated for 60 min at room temperature and then read by a TR- FRET compatible reader (Molecular Devices iD5, Molecular Devices, USA). Data analysis for compound potency determination was carried out in GraphPad Prism (GraphPad Software, La Jolla, USA).

[0211] As described in TABLE 2, below, PLPs of the present disclosure had significantly higher binding affinity for the Kelch domain of Keapl than the corresponding peptide control.

TABLE 2 - KELCH DOMAIN BINDING AFFINITIES

ND = not determined

R = L-Arginine r = D-Arginine [0212] Test inhibitors including polypeptides and polynorbornene dicarboxyimide-based polymers of the present disclosure are added at concentrations ranging from 0.001 to 1000 pM with respect to the peptide, and the percent Nrf2 activity is plotted as a function of inhibitor concentration (pM).

EXAMPLE 6: Uptake of Polynorbornene Dicarboxyimide-Based PLPs by Hepatocytes

[0213] This example shows the cell uptake of Cy5.5-labeled polynorbomene dicarboxyimide-based protein-like polymers of the present disclosure in HepG2 (liver) cells. [0214] Polynorbomene dicarboxyimide-based polymers (low and high polymerization) of the present disclosure and scrambled sequence PLP controls are dye-labeled using Cy5.5 monomer blocks added in a 1 : 15 ratio. Following the addition of the dye blocks, ethyl vinyl ether is added as a terminating agent. The resulting PLPs are purified using dialysis, sterile filtered, lyophilized, and reconcentrated in sterile water prior to cell treatment.

[0215] The dye-labeled PLPs are analyzed using SDS-PAGE. Samples are prepared for SDS-PAGE in milliQ water at a concentration of 1 mg/ml, and are added to Laemmli sample buffer at a 2:3 ratio (20 pL buffer:30 pL prepared sample) and then heated at 90 °C for 5 minutes. The resulting samples are loaded at 30 pL/well into an AnyKD mini Protean TGX ™ Precast Protein Gel along with 10 pL of the Precision Plus Protein Dual Xtra ™ 2-250kDa ladder. The gel is run in Tris/Gly/SDS Buffer at 120V until the samples reached the bottom of the gel. PLPs are visualized on the gel using an Instant Coomassie Blue Stain which is applied with shaking at 70 rpm for approximately 15 minutes. Gels are rinsed and imaged for analysis.

[0216] The PLPs labeled with Cy5.5 (excitation 683 nm, emission 703 nm) are further used to assess cellular uptake and localization. HepG2 cells are cultured using EMEM media and plated in 4-chamber 35 mm round glass-bottom dish for imaging at a cell seeding density of 15,000 cells/well and incubated for 24 hours in a 5% CO2 atmosphere at 37 °C. Cells are treated with dye-labeled PLP at concentrations of 1, 5, 10 and 50 pM with respect to peptide. Twenty -four hours after treatment, cells are stained using wheat germ agglutinin (excitation 495 nm, emission 519 nm) and Nuc blue (excitation 360 nm, emission 460 nm) to visualize the cell membrane and nucleus respectively. Imaging is performed using LEICA SP5 II laser scanning confocal microscope with a 63x oil immersion objective at 1.5x optical zoom. Slice thickness is 0.26 pm with a scan size of 1024 x 1024 pixels and a scan speed of 400 Hz. The cell nuclei (stained with NucBlu) are imaged using a 358 nm laser with a 15% laser power. Cell imaging for the membrane (stained with wheat germ agglutinin) is performed using a 488 nm laser with a 12% laser power. Cy5.5 labeled PLPs are imaged using a 633 nm laser with 12% laser power. Images are analyzed using Fiji ImageJ software.

EXAMPLE 7: Uptake of Polynorbornene Dicarboxyimide-Based PLPs by Striatal Cells

[0217] This example shows the cell uptake of Cy5.5-labeled polynorbomene dicarboxyimide-based protein-like polymers of the present disclosure in HD95/H QI 11 striatal cells (Huntington’s disease model cells).

[0218] Polynorbomene dicarboxyimide-based polymers (low and high polymerization) of the present disclosure and scrambled sequence PLP controls are dye-labeled using Cy5.5 monomer blocks added in a 1 : 15 ratio. Following the addition of the dye blocks, ethyl vinyl ether is added as a terminating agent. The resulting PLPs are purified using dialysis, sterile filtered, lyophilized, and reconcentrated in sterile water prior to cell treatment.

[0219] The dye-labeled PLPs are analyzed using SDS-PAGE. Samples are prepared for SDS-PAGE in milliQ water at a concentration of 1 mg/ml, and are added to Laemmli sample buffer at a 2:3 ratio (20 pL buffer:30 pL prepared sample) and then heated at 90 °C for 5 minutes. The resulting samples are loaded at 30 pL/well into an AnyKD mini Protean TGX ™ Precast Protein Gel along with 10 pL of the Precision Plus Protein Dual Xtra ™ 2-250kDa ladder. The gel is run in Tris/Gly/SDS Buffer at 120V until the samples reached the bottom of the gel. PLPs are visualized on the gel using an Instant Coomassie Blue Stain which is applied with shaking at 70 rpm for approximately 15 minutes. Gels are rinsed and imaged for analysis.

[0220] The PLPs labeled with Cy5.5 (excitation 683 nm, emission 703 nm) were also used to assess cellular uptake and localization. HD95/H QI 11 striatal cells were cultured using EMEM media and plated in 4-chamber 35 mm round glass-bottom dish for imaging at a cell seeding density of 15,000 cells/well and incubated for 24 hours in a 5% CO2 atmosphere at 37 °C. Cells were treated with dye-labeled PLP at concentrations of 1, 5, 10 and 50 pM with respect to peptide. Twenty-four hours after treatment, cells were stained using wheat germ agglutinin (excitation 495 nm, emission 519 nm) and Nuc blue (excitation 360 nm, emission 460 nm) to visualize the cell membrane and nucleus respectively. Imaging was performed using LEICA SP5 II laser scanning confocal microscope with a 63x oil immersion objective at 1.5x optical zoom. Slice thickness was 0.26 pm with a scan size of 1024 x 1024 pixels and a scan speed of 400 Hz. The cell nuclei (stained with NucBlu) were imaged using a 358 nm laser with a 15% laser power. Cell imaging for the membrane (stained with wheat germ agglutinin) was performed using a 488 nm laser with a 12% laser power. Cy5.5 labeled PLPs were imaged using a 633 nm laser with 12% laser power. Images were analyzed using Fiji ImageJ software.

EXAMPLE 8: Cell Permeability of Polynorbornene Dicarboxyimide-Based PLPs Across HepG2 Cell Membranes

[0221] This example shows the ability of PLPs of the present disclosure to permeate the cell membrane. To demonstrate cell permeability, the cellular uptake of Cy5.5-labeled PLPs is quantified in HepG2 cells via flow cytometry.

[0222] Cellular uptake is quantified using flow cytometry in HepG2 cells treated with Cy5.5-labeled polynorbomene dicarboxyimide-based polymers (low and high polymerization) of the present disclosure, scrambled sequence PLP controls, Cy5.5 monomer controls, and untreated controls.

[0223] Briefly, HepG2 cells are cultured using EMEM media and plated into 12-well plates at a cell seeding density of 100,000 cells/well in 1 mL media per well and incubated for 24 hours at 37 °C and 5% CO2. Cells are treated with concentrations from 0.5 pM to 3 pM with respect to dye and incubated for 24 hours at 37 °C. After incubation, media is removed, and cells are washed twice with DPBS. Cells are incubated with heparin (0.5 mg/mL in DPBS) for 5 minutes, three times, followed by a final rinse with DPBS. The DPBS is removed and 100 pL of trypsin with 0.25% EDTA is added to each well and allowed to incubate for 5 minutes at 37 °C. Cells are transferred to Eppendorf tubes and centrifuged at 1300 rpm for 5 minutes. The supernatants are removed and cells are resuspended in 200 pL of fresh DPBS. Cellular uptake is analyzed via flow cytometry using a BD FacsAria IIu™ 4-Laser flow cytometer (Becton Dickinson Inc., USA). Mean fluorescence intensity and histogram data are prepared using FlowJo vlO. EXAMPLE 9: Permeability of Polynorbornene Dicarboxyimide-Based PLPs Across the

Blood Brain Barrier

[0224] This example shows the ability of a protein-like polymer described herein to cross the blood brain barrier (BBB) to reach targets for treating diseases of the central nervous system such as neurodegenerative disease. To assess the potential of the Keapl -inhibiting PLPs to reach the CNS, human brain microvascular endothelial cells (HBEC-5i) are used in an in vitro assay to mimic the BBB in a transwell culture model.

[0225] Human cerebral microvascular endothelial cells (HBEC-5i, ATCC® CRL-3245) are cultured according to the manufacturer’s instructions (monolayer of cells on 0.1% gelatin coated T-flasks in DMEM:F12 medium supplemented with 10% FBS, 1% penicillin/ streptomycin antibiotic solution, and 40 pg/mL endothelial growth supplement (ECGS)). Cells are grown in an atmosphere of 5% CO2 at 37 °C, with the medium changed every other day. Once the cells reach confluency, they are detached with trypsin-EDTA and plated at a seeding density of 8,000 cells/well into 0.1% gelatin solution coated tissue culture inserts [transparent polyester (PET) membrane with 1.0 pm pores] for 24-well plates (BD Falcon, United States). The cells are allowed to grow for 8 days, with media changes every 2 days. On day 8, the cells are washed twice with PBS and once with DMEM:F12 medium without phenol red. PLPs are added to the apical side of the cell monolayer to final concentrations of 1, 2.5, 5, and 10 pM with respect to dye along with controls (untreated, NaF, and Cy5.5 monomer).

[0226] Cells are allowed to incubate for 24 hours at 37 °C in 5% CO2. Media is collected from the apical and basolateral chambers of each well. Translocation is assessed using a Perkin Elmer EnSpire™ multimode Plate Reader to measure the presence of Cy5.5 in the basolateral media from the outer well, and calculated as % Translocation = (fluorescence outer well - fluorescence from cell media)/(fluorescence control - fluorescence media).

EXAMPLE 10: Biocompatibility of PLPs

[0227] This example shows the biocompatibility of PLPs of the present disclosure as determined by the cell viability of IMR32 (neuroblastoma) cells treated with PLPs of the present disclosure.

[0228] IMR32 (neuroblastoma) cells from ATCC are grown in Eagle's Minimum Essential Medium (EMEM) supplemented with 10% fetal bovine serum (FBS), and 1% penicillin-streptomycin. Cells are maintained at 37 °C and 5% CO2 and cultured according to the manufacturer’s recommendations. IMR32 cells are then plated in 96-well plates at a density of 10,000 cells/well in 200 pL of media and incubated for 24 hours. Cells are treated with polynorbomene dicarboxyimide-based polymers (low and high polymerization) of the present disclosure, scrambled sequence PLP controls, and untreated controls at concentrations of 0 pM, 0.1 pM, 1 pM, 5 pM, 7.5 pM, 10 pM, 20 pM, 30 pM, 40 pM, and 50 pM with respect to peptide in triplicate. Forty-eight hours after treatment, cells are treated with 20 pL of MTS assay reagent and allowed to develop. Absorbance is measured at 490 nm using a Perkin Elmer EnSpire™ plate reader every hour after MTS addition. Viability is assessed after background subtraction from cell free control wells and calculated as relative viability based on the average of untreated control wells. Viability is reported as a percentage of untreated cells.

EXAMPLE 11: Activation of Antioxidant Response Elements (AREs) by PLPs in Hepatocytes and Other Cell Lines

[0229] This example shows the activation of an Antioxidant Response Element (ARE) for an ARE reporter HepG2 cell line, and various other ARE reporter cell lines, treated with an untreated control, a tBHQ positive control, polypeptides of the present disclosure, a low degree of polymerization polynorbornene dicarboximide-based polymer of the present disclosure, a high degree of polymerization polynorbornene dicarboximide-based polymer of the present disclosure, and a scrambled sequence PLP control.

[0230] The Antioxidant Response Element (ARE) Luciferase Reporter HepG2 Cell line, or other ARE Luciferase Reporter cell line, is used to probe Nrf2 antioxidant pathway activation. Cells are cultured in growth media (BPS bioscience) according to the manufacturer’s recommendations. Cells are plated at a seeding density of 25k cells/well into white opaque 96 well plates. PLPs and peptides are tested at concentrations ranging from 0 pM to 50 pM with respect to peptide along with controls (untreated and tBHQ positive control at 100 pM) in triplicate. Cells ae incubated for 24 hours post-treatment. ONE-step luciferase assay reagent is added at 100 pL/well, followed by rocking at room temperature for 15 min. Luminescence is assessed using a Biotek SynergyNeo2™ plate reader. Background luminescence of cell free controls wells is subtracted from test wells. ARE activation is reported as luminescence relative to the average of the untreated controls wells.

[0231] To demonstrate that the activation seen in the Antioxidant Response Element (ARE) luciferase reporter assay for a cell line is not due to stress-induced activation, an Antioxidant Response Element (ARE) luciferase reporter assay for a cell line, which is pre-treated with N-acetylcysteine to rule out stress-induced activation, is subsequently treated with (a) an untreated control, (b) a tBHQ positive control, and (c) a low degree of polymerization polynorbornene dicarboxyimide-based polymer of the present disclosure.

[0232] The Antioxidant Response Element (ARE) Reporter HepG2 Cell line, or other ARE Luciferase Reporter cell line, is used to probe Nrf2 antioxidant pathway activation. Cells are cultured in growth media (BPS bioscience) according to the manufacturer’s recommendations. Pretreatment with N-acetylcysteine (NAC) is performed to determine stress induced activation vs. targeted Keapl inhibition. Cells are plated at a seeding density of 25k cells/well into opaque 96 well plates in cell growth media dosed with 100 pg/mL of NAC. Low degree of polymerization PLPs are tested at concentrations ranging from 0 pM to 50 pM with respect to peptide along with controls (untreated and tBHQ positive control at 100 pM) in triplicate. Cells are incubated for 24 hours post-treatment. ONE-step luciferase assay reagent is added at 100 pL/well, followed by rocking at room temperature for 15 min. Luminescence is assessed using a Biotek SynergyNeo2™ plate reader. Background luminescence of cell free controls wells is subtracted from test wells. ARE activation is reported as luminescence relative to the average of the untreated controls wells.

[0233] To further demonstrate that the activation seen in the Antioxidant Response Element (ARE) luciferase reporter assay for a HepG2 cell line, or other ARE Luciferase Reporter cell line, is not due to stress-induced activation, an MTS cell viability assay is performed over a concentration range of 0 pM to 100 pM for a low degree of polymerization polymer of the present disclosure, a high degree of polymerization polymer of the present disclosure, polypeptides of the present disclosure, as well as untreated, vehicle and tBHQ positive controls.

[0234] Cells are plated at a seeding density of 25k cells/well into 96 well plates in cell growth media and allowed to incubate for 24 hours. Cells are treated with peptide or PLPs over a range of concentrations (i.e. 0 pM to 100 pM with respect to peptide) at n=3. After 24 hours, 10 pL of MTS reagent is added to each well, and the cells are incubated for four hours at 37 °C. Absorbance is measured at 490 nm using a Perkin Elmer EnSpire™ plate reader every hour after MTS addition. Viability is assessed after background subtraction from cell free control wells and calculated as relative viability based on the average of untreated control wells. Viability is reported as a percentage of untreated cells EXAMPLE 12: Impact of Polymer Backbones on Cell Viability

[0235] This example shows that displaying peptides on a different backbone does not impact cell viability in the Antioxidant Response Element (ARE)-Luciferase Reporter HepG2 cell line, or other ARE-Luciferase Reporter cell line.

[0236] To demonstrate that the PLPs are well-tolerated in the ARE-Luc Reporter HepG2 cell line, or other ARE-Luciferase Reporter cell line, an MTS cell viability assay is performed over a concentration range of 0 pM to 100 pM for a (meth)acrylamide-based brush polymer (“RAFT PLP”) comprising a polypeptide having a sequence of SEQ ID NO: 1, SEQ ID NO:2, or any sequence of Table 1, as well as untreated, vehicle and tBHQ positive controls.

[0237] Cells are plated at a seeding density of 25k cells/well into 96 well plates in cell growth media and allowed to incubate for 24 hours. Cells are treated with peptide or PLPs over a range of concentrations (i.e. 0 pM to 100 pM with respect to peptide) at n=3. After 24 hours, 10 mL of MTS reagent is added to each well, and the cells are incubated for four hours at 37 °C. Absorbance is measured at 490 nm using a Perkin Elmer EnSpire™ plate reader every hour after MTS addition. Viability is assessed after background subtraction from cell- free control wells and calculated as relative viability based on the average of untreated control wells. Viability is reported as a percentage of untreated cells.

INCORPORATION BY REFERENCE

[0238] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

EQUIVALENTS

[0239] The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.