Analgesic Polypeptides

Abstract

Analgesic peptides are provided. Formulations comprising any one of the analgesic peptides and a pharmaceutically acceptable excipient are also provided. Methods for treating or preventing pain in a subject in need thereof are also provided, comprising administering to the subject an effective amount of any one of the analgesic peptides. In one embodiment, an artificial polypeptide of formula (VI) is provided: XY(VI), wherein X is a moiety comprising a variant of the sequence of SEQ ID NO: 1, wherein the variant is characterized by having at least one, two, three, four, five, six, seven, eight, or nine Ds in SEQ ID NO: 1 mutated to S, and / or at least one, two, three, four, five, or six Es in SEQ ID NO: 1 mutated to T; and Y is a moiety comprising a variant of the sequence of SEQ ID NO: 2, wherein the variant is characterized by having at least one, two, three, four, or five Cs in SEQ ID NO: 2 mutated to A.

Description

[Technical Field]

[0001] cross reference This application claims priority to PCT Application No. PCT / CN2022 / 119040, filed September 15, 2022, and PCT Application No. PCT / CN2023 / 081352, filed March 14, 2023, the contents of which are incorporated herein by reference in their entireties. [Background technology]

[0002] background According to the definition provided by the International Association for the Study of Pain (IASP) in 2020, pain is known as an unpleasant sensory and emotional experience associated with or similar to that associated with actual or potential tissue damage. Pain is always a personal experience influenced to varying degrees by biological, psychological, and social factors. Although pain usually plays an adaptive role, it can have adverse effects on functioning and social and psychological well-being. Pain can be a symptom caused by a disease or can be considered a separate disease.

[0003] The classification of pain has always been extremely complex. Generally, pain can be divided into three major categories according to the course of the disease: acute pain (less than 3 months in duration), chronic pain (greater than 3 to 6 months in duration), and transitional pain (3 to 6 months in duration). Chronic pain can be further divided into nociceptive pain (caused by persistent inflammation and tissue damage), neuropathic pain (caused by nerve damage), and mixed pain (a pain state with characteristics of both nociceptive and neuropathic pain).

[0004] Current clinical measures for pain management include drug therapy, minimally invasive intervention, neuromodulation, surgery and other treatment methods. Among them, drug therapy is considered the most basic and commonly used treatment method for pain. To date, there is still an unmet need in the medical community for drugs that effectively manage pain. Summary of the Invention [Means for solving the problem]

[0005] overview The present disclosure provides an analgesic peptide.Also provided is a formulation comprising any one of the analgesic peptides and a pharmaceutically acceptable excipient.Also provided is a method for treating or preventing pain in a subject in need thereof, comprising administering an effective amount of any one of the analgesic peptides to the subject.

[0006] In one embodiment, an artificial polypeptide of formula (VI) is provided: XY(VI), wherein X is a moiety comprising a variant of the sequence of SEQ ID NO: 1, characterized in that the variant has at least one, two, three, four, five, six, seven, eight or nine Ds in SEQ ID NO: 1 mutated to S, and / or at least one, two, three, four, five or six Es in SEQ ID NO: 1 mutated to T; and Y is a portion comprising a variant of the sequence of SEQ ID NO: 2, wherein the variant is characterized by having at least one, two, three, four or five Cs in SEQ ID NO: 2 mutated to A).

[0007] In some embodiments, X comprises a sequence having at least 70% identity to SEQ ID NO: 1, and / or X comprises a sequence having at most 95% identity to SEQ ID NO: 1. In some embodiments, X comprises a sequence having at least 70% identity to SEQ ID NO: 1. In some embodiments, X comprises a sequence having at most 95% identity to SEQ ID NO: 1. In some embodiments, the total number of R, K, T, A, N, Q, D, E, S, and G in X is greater than 30 and / or the total number of W, Y, F, M, L, I, and V in X is 20 or less. In some embodiments, the total number of R, K, T, A, N, Q, D, E, S, and G in X is greater than 30. In some embodiments, the total number of W, Y, F, M, L, I, and V in X is 20 or less. In some embodiments, X comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 80-83, X comprises a sequence that is any one selected from SEQ ID NOs: 80-83, or X is a sequence that is any one selected from SEQ ID NOs: 80-83. In some embodiments, X comprises a sequence that is at least 80% identity to any one selected from SEQ ID NOs: 80-83. In some embodiments, X comprises a sequence that is any one selected from SEQ ID NOs: 80-83. In some embodiments, X is a sequence that is any one selected from SEQ ID NOs: 80-83.

[0008] In some embodiments, Y comprises a sequence having at least 80% identity to SEQ ID NO:2, and / or Y comprises a sequence having up to 95% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 80% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having up to 95% identity to SEQ ID NO:2. In some embodiments, at least 50% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, the total number of R, K, T, A, N, Q, D, E, S, and G in Y is greater than 10 and / or the total number of W, Y, F, M, L, I, and V in Y is 20 or less. In some embodiments, the total number of R, K, T, A, N, Q, D, E, S, and G in Y is greater than 10. In some embodiments, the total number of W, Y, F, M, L, I, and V in Y is 20 or less. In some embodiments, Y comprises a sequence having at least 80% identity to SEQ ID NO: 3, Y comprises the sequence of SEQ ID NO: 3, or Y is the sequence of SEQ ID NO: 3. In some embodiments, Y comprises a sequence having at least 80% identity to SEQ ID NO: 3. In some embodiments, Y comprises the sequence of SEQ ID NO: 3. In some embodiments, Y is the sequence of SEQ ID NO: 3.

[0009] In some embodiments, the artificial polypeptide comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 90-93, the artificial polypeptide comprises a sequence that is any one selected from SEQ ID NOs: 90-93, or the artificial polypeptide is a sequence that is any one selected from SEQ ID NOs: 90-93. In some embodiments, the artificial polypeptide comprises a sequence that is at least 80% identity to any one selected from SEQ ID NOs: 90-93. In some embodiments, the artificial polypeptide comprises a sequence that is any one selected from SEQ ID NOs: 90-93. In some embodiments, the artificial polypeptide is a sequence that is any one selected from SEQ ID NOs: 90-93.

[0010] In another aspect, there is provided an artificial polypeptide of formula (VII): XY(VII), wherein X is a portion of the sequence of SEQ ID NO: 1 that comprises a variant, the variant being characterized by having at least one, two, three, four or five amino acid insertions compared to SEQ ID NO: 1; and Y is a moiety containing 10 to 30 amino acids, and Y includes a sequence having at least 15 consecutive AA of SEQ ID NO: 2).

[0011] In some embodiments, the amino acid insertion is located N-terminal to X and / or the inserted amino acid is M. In some embodiments, the amino acid insertion is located N-terminal to X. In some embodiments, the inserted amino acid is M.

[0012] In some embodiments, at least 50% of the amino acids in X are selected from R, K, N, D, Q, E, and H, and / or up to 60% of the amino acids in X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 50% of the amino acids in X are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 60% of the amino acids in X are selected from R, K, N, D, Q, E, and H. In some embodiments, the total number of E or D in X is at least 8, and / or the total number of E or D in X is at most 15. In some embodiments, the total number of E or D in X is at least 8. In some embodiments, the total number of E or D in X is at most 15. In some embodiments, the total number of R, K, T, A, N, Q, D, E, S, and G in X is greater than 30 and / or the total number of W, Y, F, M, L, I, and V in X is no more than 20. In some embodiments, the total number of R, K, T, A, N, Q, D, E, S, and G in X is greater than 30. In some embodiments, the total number of W, Y, F, M, L, I, and V in X is 20 or less. In some embodiments, X comprises a sequence having at least 80% identity to SEQ ID NO: 96, X comprises the sequence of SEQ ID NO: 96, or X is the sequence of SEQ ID NO: 96. In some embodiments, X comprises a sequence having at least 80% identity to SEQ ID NO: 96. In some embodiments, X comprises the sequence of SEQ ID NO: 96. In some embodiments, X is the sequence of SEQ ID NO: 96.

[0013] In some embodiments, Y, is a moiety comprising a variant of the sequence of SEQ ID NO:2, wherein the variant is characterized by having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids truncated relative to SEQ ID NO:2, optionally wherein the at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids truncated relative to SEQ ID NO:2. In some embodiments, Y, is a moiety comprising a variant of the sequence of SEQ ID NO:2, wherein the variant is characterized by having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids truncated relative to SEQ ID NO:2. In some embodiments, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid truncations are located at the C-terminus of Y. In some embodiments, Y comprises 15-25 amino acids, Y comprises 18-25 amino acids, or Y comprises 20-25 amino acids. In some embodiments, Y comprises 15-25 amino acids. In some embodiments, Y comprises 18-25 amino acids. In some embodiments, Y comprises 20-25 amino acids. In some embodiments, 40-65% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, the total number of R, K, T, A, N, Q, D, E, S, and G in Y is 10 or less, and / or the total number of W, Y, F, M, L, I, and V in Y is 15 or less. In some embodiments, the total number of R, K, T, A, N, Q, D, E, S, and G in Y is 10 or less. In some embodiments, the total number of W, Y, F, M, L, I, and V in Y is 15 or less. In some embodiments, Y comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 97-103, Y comprises a sequence that is any one selected from SEQ ID NOs: 97-103, or Y is a sequence that is any one selected from SEQ ID NOs: 97-103. In some embodiments, Y comprises a sequence that is at least 80% identity to any one selected from SEQ ID NOs: 97-103.In some embodiments, Y comprises a sequence that is any one selected from SEQ ID NOs: 97 to 103. In some embodiments, Y is a sequence that is any one selected from SEQ ID NOs: 97 to 103.

[0014] In some embodiments, the artificial polypeptide comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 104-110, the artificial polypeptide comprises a sequence that is any one selected from SEQ ID NOs: 104-110, or the artificial polypeptide is a sequence that is any one selected from SEQ ID NOs: 104-110. In some embodiments, the artificial polypeptide comprises a sequence that is at least 80% identity to any one selected from SEQ ID NOs: 104-110. In some embodiments, the artificial polypeptide comprises a sequence that is any one selected from SEQ ID NOs: 104-110. In some embodiments, the artificial polypeptide is a sequence that is any one selected from SEQ ID NOs: 104-110.

[0015] In another aspect, there is provided an artificial polypeptide of formula (I): XY(I), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1; Y is a moiety comprising 10 to 50 amino acids, at least 50% of which are selected from I, V, L, F, C, M and A; Y contains a total number of cysteines (C) of less than 5 wherein the mutant has at least 1, 2, 3, 4, 5, 6, 7, 8 or 9 D in X mutated to S, and / or at least 1, 2, 3, 4, 5 or 6 E in X mutated to T.

[0016] In some embodiments, at least 20% of the amino acids of X are selected from R, K, N, D, Q, E, and H; at least 30% of the amino acids of X are selected from R, K, N, D, Q, E, and H; up to 90% of the amino acids of X are selected from R, K, N, D, Q, E, and H; and / or up to 80% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 20% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 30% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 90% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 80% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, X comprises a sequence having at least 70% identity to SEQ ID NO:1.

[0017] In some embodiments, Y, comprises a total number of cysteines (C) less than 4, or Y, comprises a total number of cysteines (C) less than 3. In some embodiments, Y, comprises a total number of cysteines (C) less than 4. In some embodiments, Y, comprises a total number of cysteines (C) less than 3. In some embodiments, the total number of hydrophobic amino acids in Y, is greater than 8, the total number of hydrophobic amino acids in Y, is greater than 12, the total number of hydrophobic amino acids in Y, is greater than 15, and / or the total number of hydrophilic amino acids in Y is 5 or less. In some embodiments, the total number of hydrophobic amino acids in Y, is greater than 8. In some embodiments, the total number of hydrophobic amino acids in Y, is greater than 12. In some embodiments, the total number of hydrophobic amino acids in Y, is greater than 15. In some embodiments, the total number of hydrophilic amino acids in Y, is 5 or less. In some embodiments, Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-15, 58-61 and 84-85, or Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-18, 58-61 and 84-85. In some embodiments, Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-15, 58-61 and 84-85. In some embodiments, Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-18, 58-61 and 84-85.

[0018] In another aspect, an artificial polypeptide of formula (II) XY(II), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1; Y is a moiety comprising 10 to 50 amino acids, at least 50% of which are selected from I, V, L, F, C, M and A; Y comprises a sequence having at most 90% identity to SEQ ID NO: 2 wherein the mutant is characterized by having at least 1, 2, 3, 4, 5, 6, 7, 8 or 9 D in X mutated to S, and / or at least 1, 2, 3, 4, 5 or 6 E in X mutated to T.

[0019] In some embodiments, at least 20% of the amino acids of X are selected from R, K, N, D, Q, E, and H; at least 30% of the amino acids of X are selected from R, K, N, D, Q, E, and H; up to 90% of the amino acids of X are selected from R, K, N, D, Q, E, and H; and / or up to 80% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 20% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 30% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 90% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 80% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, X comprises a sequence having at least 70% identity to SEQ ID NO:1.

[0020] In some embodiments, Y, comprises a sequence having up to 80% identity to SEQ ID NO:2, or Y, comprises a sequence having up to 70% identity to SEQ ID NO:2. In some embodiments, Y, comprises a sequence having up to 80% identity to SEQ ID NO:2. In some embodiments, Y, comprises a sequence having up to 70% identity to SEQ ID NO:2. In some embodiments, the total number of hydrophobic amino acids in Y, is greater than 8, the total number of hydrophobic amino acids in Y, is greater than 12, the total number of hydrophobic amino acids in Y, is greater than 15, and / or the total number of hydrophilic amino acids in Y, is 5 or less. In some embodiments, the total number of hydrophobic amino acids in Y, is greater than 8. In some embodiments, the total number of hydrophobic amino acids in Y, is greater than 12. In some embodiments, the total number of hydrophobic amino acids in Y, is greater than 15. In some embodiments, the total number of hydrophilic amino acids in Y, is 5 or less. In some embodiments, Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 16-18, or Y comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 16-18. In some embodiments, Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 16-18. In some embodiments, Y comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 16-18.

[0021] In another aspect, an artificial polypeptide of formula (III) XY(III), wherein X is a moiety comprising 40 to 65 amino acids, at least 50% of which are selected from H, R, K, D, Q, N, and E; Y is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 2, The total number of H, R, K, D, Q, N, and E in X is less than 33. wherein the mutant is characterized by having at least 1, 2, 3, 4, 5, 6, 7, 8 or 9 D in X mutated to S, and / or at least 1, 2, 3, 4, 5 or 6 E in X mutated to T.

[0022] In some embodiments, at least 20% of the amino acids of X are selected from R, K, N, D, Q, E, and H; at least 30% of the amino acids of X are selected from R, K, N, D, Q, E, and H; up to 90% of the amino acids of X are selected from R, K, N, D, Q, E, and H; and / or up to 80% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 20% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 30% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 90% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 80% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, X comprises a sequence having at least 70% identity to SEQ ID NO: 1. In some embodiments, the total number of H, R, K, D, Q, N, and E in X is less than 30, the total number of H, R, K, D, Q, N, and E in X is less than 25, or the total number of H, R, K, D, Q, N, and E in X is less than 20. In some embodiments, the total number of H, R, K, D, Q, N, and E in X is less than 30. In some embodiments, the total number of H, R, K, D, Q, N, and E in X is less than 25. In some embodiments, the total number of H, R, K, D, Q, N, and E in X is less than 20. In some embodiments, the total number of hydrophilic amino acids in X is greater than 10, the total number of hydrophilic amino acids in X is greater than 15, the total number of hydrophilic amino acids in X is greater than 20, the total number of hydrophilic amino acids in X is greater than 25, the total number of hydrophilic amino acids in X is 15 or less, and / or the total number of hydrophobic amino acids in X is 10 or less. In some embodiments, the total number of hydrophilic amino acids in X is greater than 10. In some embodiments, the total number of hydrophilic amino acids in X is greater than 15. In some embodiments, the total number of hydrophilic amino acids in X is greater than 20. In some embodiments, the total number of hydrophilic amino acids in X is greater than 25. In some embodiments, the total number of hydrophobic amino acids in X is 15 or less. In some embodiments, the total number of hydrophobic amino acids in X is 10 or less.

[0023] In some embodiments, Y comprises a sequence having at least 90% identity to SEQ ID NO: 2, or Y comprises the sequence of SEQ ID NO: 2. In some embodiments, Y comprises a sequence having at least 90% identity to SEQ ID NO: 2. In some embodiments, Y comprises the sequence of SEQ ID NO: 2. In some embodiments, at least 50% of the amino acids of Y are selected from I, V, L, F, C, M and A.

[0024] In another aspect, an artificial polypeptide of formula (IV) XY(IV), wherein X is a moiety comprising 40 to 65 amino acids, at least 50% of which are selected from H, R, K, D, Q, N, and E; Y is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 2, X comprises a sequence having at most 90% identity to SEQ ID NO: 1 wherein the mutant is characterized by having at least 1, 2, 3, 4, 5, 6, 7, 8 or 9 D in X mutated to S, and / or at least 1, 2, 3, 4, 5 or 6 E in X mutated to T.

[0025] In some embodiments, at least 20% of the amino acids of X are selected from R, K, N, D, Q, E, and H; at least 30% of the amino acids of X are selected from R, K, N, D, Q, E, and H; up to 90% of the amino acids of X are selected from R, K, N, D, Q, E, and H; and / or up to 80% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 20% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 30% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 90% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 80% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, X comprises a sequence having at least 70% identity to SEQ ID NO: 1. In some embodiments, the total number of hydrophilic amino acids in X is greater than 10, greater than 15, greater than 20, greater than 25, the total number of hydrophilic amino acids in X is 15 or less, and / or the total number of hydrophilic amino acids in X is 10 or less. In some embodiments, the total number of hydrophilic amino acids in X is greater than 10. In some embodiments, the total number of hydrophilic amino acids in X is greater than 15. In some embodiments, the total number of hydrophilic amino acids in X is greater than 20. In some embodiments, the total number of hydrophilic amino acids in X is greater than 25. In some embodiments, the total number of hydrophilic amino acids in X is 15 or less. In some embodiments, the total number of hydrophilic amino acids in X is 10 or less.

[0026] In some embodiments, Y comprises a sequence having at least 90% identity to SEQ ID NO: 2, or Y comprises the sequence of SEQ ID NO: 2. In some embodiments, Y comprises a sequence having at least 90% identity to SEQ ID NO: 2. In some embodiments, Y comprises the sequence of SEQ ID NO: 2. In some embodiments, at least 50% of the amino acids of Y are selected from I, V, L, F, C, M and A.

[0027] In another aspect, an artificial polypeptide of formula (V) XY(V), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1; Y is a moiety containing 10 to 30 amino acids, and Y includes a sequence having at least 10 consecutive AA of SEQ ID NO: 2. wherein the mutant is characterized by having at least 1, 2, 3, 4, 5, 6, 7, 8 or 9 D in X mutated to S, and / or at least 1, 2, 3, 4, 5 or 6 E in X mutated to T.

[0028] In some embodiments, at least 20% of the amino acids of X are selected from R, K, N, D, Q, E, and H; at least 30% of the amino acids of X are selected from R, K, N, D, Q, E, and H; up to 90% of the amino acids of X are selected from R, K, N, D, Q, E, and H; and / or up to 80% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 20% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 30% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 90% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 80% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, X comprises a sequence having at least 70% identity to SEQ ID NO:1.

[0029] In some embodiments, Y comprises 10-25 amino acids, Y comprises 10-20 amino acids, or Y comprises 10-15 amino acids. In some embodiments, Y comprises 10-25 amino acids. In some embodiments, Y comprises 10-20 amino acids. In some embodiments, Y comprises 10-15 amino acids. In some embodiments, Y comprises a sequence having up to 80% identity to SEQ ID NO:2, Y comprises a sequence having up to 70% identity to SEQ ID NO:2, or Y comprises a sequence having up to 50% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having up to 80% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having up to 70% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having up to 50% identity to SEQ ID NO:2.

[0030] In another aspect, there is provided a formulation comprising the aforementioned artificial polypeptide of formula (VI) or (VII) or a variant of the artificial polypeptide of formula (I), (II), (III), (IV) or (V) and a pharmaceutically acceptable excipient.

[0031] In another aspect, a method for treating or preventing pain in a subject in need thereof is provided, comprising: an effective amount of an artificial polypeptide of formula (I): XY(I), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1; and Y is a moiety comprising 10 to 50 amino acids, at least 50% of which are selected from I, V, L, F, C, M and A; Y contains a total number of cysteines (C) of less than 5 to a subject.

[0032] In some embodiments, X comprises a sequence having at least 90% identity to SEQ ID NO:1, X comprises a sequence having at least 95% identity to SEQ ID NO:1, or X comprises the sequence of SEQ ID NO:1. In some embodiments, X comprises a sequence having at least 90% identity to SEQ ID NO:1. In some embodiments, X comprises a sequence having at least 95% identity to SEQ ID NO:1. In some embodiments, X comprises the sequence of SEQ ID NO:1. In some embodiments, at least 50% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, X comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs:81-83.

[0033] In some embodiments, Y, comprises a total number of cysteines (C) of less than 4, Y, comprises a total number of cysteines (C) of less than 3, or Y, comprises a total number of cysteines (C) of less than 2. In some embodiments, Y, comprises a total number of cysteines (C) of less than 4. In some embodiments, Y, comprises a total number of cysteines (C) of less than 3. In some embodiments, Y, comprises a total number of cysteines (C) of less than 2. In some embodiments, the total number of hydrophobic amino acids in Y, is greater than 8, the total number of hydrophobic amino acids in Y, is greater than 12, the total number of hydrophobic amino acids in Y, is greater than 15, and / or the total number of hydrophilic amino acids in Y, is 5 or less. In some embodiments, the total number of hydrophobic amino acids in Y, is greater than 8. In some embodiments, the total number of hydrophobic amino acids in Y, is greater than 12. In some embodiments, the total number of hydrophobic amino acids in Y, is greater than 15. In some embodiments, the total number of hydrophilic amino acids in Y, is 5 or less. In some embodiments, Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-15, 58-61 and 84-85, or Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-18, 58-61 and 84-85. In some embodiments, Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-15, 58-61 and 84-85. In some embodiments, Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-18, 58-61 and 84-85.

[0034] In some embodiments, the polypeptide comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 29-41, 54-57, 75 and 91-95.

[0035] In another aspect, a method for treating or preventing pain in a subject in need thereof is provided, comprising: an effective amount of an artificial polypeptide of formula (II): XY(II), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1; and Y is a moiety comprising 10 to 50 amino acids, at least 50% of which are selected from I, V, L, F, C, M and A; Y comprises a sequence having at most 90% identity to SEQ ID NO: 2 to a subject.

[0036] In some embodiments, X comprises a sequence having at least 90% identity to SEQ ID NO: 1, X comprises a sequence having at least 95% identity to SEQ ID NO: 1, or X comprises the sequence of SEQ ID NO: 1. In some embodiments, X comprises a sequence having at least 90% identity to SEQ ID NO: 1. In some embodiments, X comprises a sequence having at least 95% identity to SEQ ID NO: 1. In some embodiments, X comprises the sequence of SEQ ID NO: 1. In some embodiments, at least 50% of the amino acids of X are selected from R, K, N, D, Q, E, and H.

[0037] In some embodiments, Y comprises a sequence having up to 80% identity to SEQ ID NO:2, Y comprises a sequence having up to 70% identity to SEQ ID NO:2, or Y comprises a sequence having up to 50% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having up to 80% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having up to 70% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having up to 50% identity to SEQ ID NO:2. In some embodiments, the total number of hydrophobic amino acids in Y is greater than 8, the total number of hydrophobic amino acids in Y is greater than 12, the total number of hydrophobic amino acids in Y is greater than 15, and / or the total number of hydrophilic amino acids in Y is 5 or less. In some embodiments, the total number of hydrophobic amino acids in Y is greater than 8. In some embodiments, the total number of hydrophobic amino acids in Y is greater than 12. In some embodiments, the total number of hydrophobic amino acids in Y is greater than 15. In some embodiments, the total number of hydrophilic amino acids in Y is 5 or less. In some embodiments, Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 16-18, or Y comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 16-18. In some embodiments, Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 16-18. In some embodiments, Y comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 16-18.

[0038] In some embodiments, the polypeptide comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 42-44.

[0039] In another aspect, a method for treating or preventing pain in a subject in need thereof is provided, comprising: an effective amount of an artificial polypeptide of formula (III): XY(III), wherein X is a moiety comprising 40 to 65 amino acids, at least 50% of which are selected from H, R, K, D, Q, N, and E; and Y is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 2, The total number of H, R, K, D, Q, N, and E in X is less than 33. to a subject.

[0040] In some embodiments, Y comprises a sequence having at least 90% identity to SEQ ID NO:2, Y comprises a sequence having at least 95% identity to SEQ ID NO:2, or Y comprises the sequence of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 90% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 95% identity to SEQ ID NO:2. In some embodiments, Y comprises the sequence of SEQ ID NO:2. In some embodiments, at least 50% of the amino acids of Y are selected from I, V, L, F, C, M, and A.

[0041] In some embodiments, the total number of H, R, K, D, Q, N, and E in X is less than 30, the total number of H, R, K, D, Q, N, and E in X is less than 25, or the total number of H, R, K, D, Q, N, and E in X is less than 20. In some embodiments, the total number of H, R, K, D, Q, N, and E in X is less than 30. In some embodiments, the total number of H, R, K, D, Q, N, and E in X is less than 25. In some embodiments, the total number of H, R, K, D, Q, N, and E in X is less than 20. In some embodiments, the total number of hydrophilic amino acids in X is greater than 10, the total number of hydrophilic amino acids in X is greater than 15, the total number of hydrophilic amino acids in X is greater than 20, the total number of hydrophilic amino acids in X is greater than 25, the total number of hydrophilic amino acids in X is 15 or less, and / or the total number of hydrophobic amino acids in X is 10 or less. In some embodiments, the total number of hydrophilic amino acids in X is greater than 10. In some embodiments, the total number of hydrophilic amino acids in X is greater than 15. In some embodiments, the total number of hydrophilic amino acids in X is greater than 20. In some embodiments, the total number of hydrophilic amino acids in X is greater than 25. In some embodiments, the total number of hydrophobic amino acids in X is 15 or less. In some embodiments, the total number of hydrophobic amino acids in X is 10 or less. In some embodiments, X comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 23-27, or X comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 23-27. In some embodiments, X comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 23-27. In some embodiments, X comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 23-27.

[0042] In some embodiments, the polypeptide comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 49-53.

[0043] In another aspect, a method for treating or preventing pain in a subject in need thereof is provided, comprising: an effective amount of an artificial polypeptide of formula (IV): XY(IV), wherein X is a moiety comprising 40 to 65 amino acids, at least 50% of which are selected from H, R, K, D, Q, N, and E; and Y is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 2, X comprises a sequence having at most 90% identity to SEQ ID NO: 1 to a subject.

[0044] In some embodiments, X comprises a sequence having up to 80% identity to SEQ ID NO:1, X comprises a sequence having up to 70% identity to SEQ ID NO:1, or X comprises a sequence having up to 50% identity to SEQ ID NO:1. In some embodiments, X comprises a sequence having up to 80% identity to SEQ ID NO:1. In some embodiments, X comprises a sequence having up to 70% identity to SEQ ID NO:1. In some embodiments, X comprises a sequence having up to 50% identity to SEQ ID NO:1. In some embodiments, the total number of hydrophilic amino acids in X is greater than 10, the total number of hydrophilic amino acids in X is greater than 15, the total number of hydrophilic amino acids in X is greater than 20, the total number of hydrophilic amino acids in X is greater than 25, the total number of hydrophilic amino acids in X is 15 or less, and / or the total number of hydrophobic amino acids in X is 10 or less. In some embodiments, the total number of hydrophilic amino acids in X is greater than 10. In some embodiments, the total number of hydrophilic amino acids in X is greater than 15. In some embodiments, the total number of hydrophilic amino acids in X is greater than 20. In some embodiments, the total number of hydrophilic amino acids in X is greater than 25. In some embodiments, the total number of hydrophobic amino acids in X is 15 or less. In some embodiments, the total number of hydrophobic amino acids in X is 10 or less. In some embodiments, X comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 19-22 and 76-79, or X comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 19-22 and 76-79. In some embodiments, X comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 19-22 and 76-79. In some embodiments, X comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 19-22 and 76-79.

[0045] In some embodiments, Y comprises a sequence having at least 90% identity to SEQ ID NO:2, Y comprises a sequence having at least 95% identity to SEQ ID NO:2, or Y comprises the sequence of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 90% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 95% identity to SEQ ID NO:2. In some embodiments, Y comprises the sequence of SEQ ID NO:2. In some embodiments, at least 50% of the amino acids of Y are selected from I, V, L, F, C, M, and A.

[0046] In some embodiments, the polypeptide comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 45-48 and 86-89.

[0047] In another aspect, a method for treating or preventing pain in a subject in need thereof is provided, comprising: an effective amount of an artificial polypeptide of formula (V): XY(V), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1; and Y is a moiety containing 10 to 30 amino acids, Y comprises a sequence having at least 10 consecutive AA of SEQ ID NO:2 to a subject.

[0048] In some embodiments, X comprises a sequence having at least 90% identity to SEQ ID NO:1, X comprises a sequence having at least 95% identity to SEQ ID NO:1, or X comprises the sequence of SEQ ID NO:1. In some embodiments, X comprises a sequence having at least 90% identity to SEQ ID NO:1. In some embodiments, X comprises a sequence having at least 95% identity to SEQ ID NO:1. In some embodiments, X comprises the sequence of SEQ ID NO:1. In some embodiments, X comprises the sequence of SEQ ID NO:1. In some embodiments, at least 50% of the amino acids of X are selected from R, K, N, D, Q, E, and H. In some embodiments, X comprises a sequence having at least 80% identity to SEQ ID NO:96, X comprises a sequence having at least 90% identity to SEQ ID NO:96, X comprises a sequence having at least 95% identity to SEQ ID NO:96, or X comprises the sequence of SEQ ID NO:96. In some embodiments, X comprises a sequence having at least 80% identity to SEQ ID NO:96. In some embodiments, X comprises a sequence having at least 90% identity to SEQ ID NO:96. In some embodiments, X comprises a sequence having at least 95% identity to SEQ ID NO: 96. In some embodiments, X comprises the sequence of SEQ ID NO: 96.

[0049] In some embodiments, Y comprises 10-25 amino acids, Y comprises 10-20 amino acids, or Y comprises 10-15 amino acids. In some embodiments, Y comprises 10-25 amino acids. In some embodiments, Y comprises 10-20 amino acids. In some embodiments, Y comprises 10-15 amino acids.

[0050] In some embodiments, Y comprises a sequence having at most 80% identity to SEQ ID NO:2, Y comprises a sequence having at most 70% identity to SEQ ID NO:2, or Y comprises a sequence having at most 50% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 80% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 70% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 50% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs:97-103, Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs:97-103, Y comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs:97-103, or Y comprises a sequence that is any one selected from SEQ ID NOs:97-103. In some embodiments, Y comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 97-103. In some embodiments, Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 97-103. In some embodiments, Y comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 97-103. In some embodiments, Y comprises a sequence that is any one selected from SEQ ID NOs: 97-103.

[0051] In some embodiments, the polypeptide comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 53-56 and 104-110.

[0052] In another aspect, a method for treating or preventing pain in a subject in need thereof is provided, comprising administering to the subject an effective amount of an artificial polypeptide of formula (VI) or (VII), or a variant of an artificial polypeptide of formula (I), (II), (III), (IV) or (V), as described herein above.

[0053] In some embodiments, the pain is at least one selected from the group consisting of acute pain, chronic pain, and transitional pain.

[0054] In some embodiments, the acute pain is at least one selected from the group consisting of pain associated with an acute injury, acute inflammatory pain, and headache.

[0055] In some embodiments, the pain associated with an acute injury is acute post-operative pain.

[0056] In some embodiments, the chronic pain is at least one selected from the group consisting of nociceptive pain, neuropathic pain, and mixed pain.

[0057] In some embodiments, the nociceptive pain is at least one selected from the group consisting of abdominal pain, anal fissure pain, bladder pain, complex regional pain syndrome, breast pain, intestinal spasm, bladder pain syndrome, joint pain, musculoskeletal pain, muscle pain, myofascial pain syndrome, nociceptive bone pain, pain associated with pancreatitis, polymyalgia rheumatica, chronic post-operative pain, renal pain, somatic pain, tendon pain (teinodynia), ligament pain (desmalgia), chronic trauma pain, pain associated with fractures, and visceral pain.

[0058] In some embodiments, the breast pain is cyclical breast pain.

[0059] In some embodiments, the renal pain is renal colic.

[0060] In some embodiments, the pain associated with a fracture is pain associated with a spinal fracture.

[0061] In some embodiments, the mixed pain is at least one selected from the group consisting of arthritis pain, back pain, cancer pain, dental pain, fibromyalgia, chronic inflammatory pain, lower back pain, neck pain, and eye pain.

[0062] In some embodiments, the arthritis pain is at least one selected from the group consisting of osteoarthritis pain, rheumatoid arthritis pain, and gout pain.

[0063] In some embodiments, the cancer pain is tumor-associated cancer pain.

[0064] In some embodiments, the tumor-associated cancer pain is at least one selected from the group consisting of cancer-associated nerve pain, cancer-associated bone pain, cancer-associated soft tissue pain, and cancer-associated referred pain.

[0065] In some embodiments, the cancer-associated bone pain is at least one selected from the group consisting of bone pain associated with bone cancer and bone pain associated with bone metastatic tumors.

[0066] In some embodiments, the bone pain associated with bone cancer is at least one selected from the group consisting of bone pain associated with chondrosarcoma, bone pain associated with Ewing's sarcoma, bone pain associated with malignant fibrous histiocytoma of bone, bone pain associated with osteosarcoma, and bone pain associated with fibrochondromeschymoma of bone.

[0067] In some embodiments, the cancer pain is cancer pain associated with a diagnostic and / or therapeutic procedure.

[0068] In some embodiments, the cancer pain associated with a diagnostic and / or therapeutic procedure is cancer-associated phantom pain. In some embodiments, the cancer pain associated with a diagnostic and / or therapeutic procedure is chemotherapy-associated cancer pain. In some embodiments, the chemotherapy-associated cancer pain is cancer pain associated with chemotherapy-induced peripheral neuropathy (CIPN). In some embodiments, the chemotherapy is administered by administering a cytotoxic agent to a subject in need thereof. In some embodiments, the cytotoxic agent is at least one selected from the group consisting of platinum anticancer agents (e.g., cisplatin, carboplatin, nedaplatin, and oxaliplatin), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), taxanes (e.g., paclitaxel and docetaxel), and proteasome or angiogenesis inhibitors (e.g., bortezomib, carfilzomib, and thalidomide).

[0069] In some embodiments, the ocular pain is at least one selected from the group consisting of ocular nociceptive pain and ocular neuropathic pain.

[0070] In some embodiments, the ocular nociceptive pain is at least one selected from the group consisting of eye pain associated with injury, eye pain associated with surgery, eye pain associated with contact lens wear, and eye pain associated with the irritation of a foreign body.

[0071] In some embodiments, the ocular neuropathic pain is at least one selected from the group consisting of ocular pain associated with allergies, ocular pain associated with infections, ocular pain associated with inflammation, ocular pain associated with chronic ocular surface disease, postoperative ocular neuropathic pain, ocular pain associated with toxic keratopathy, ocular pain associated with radiation, ocular pain associated with ultraviolet light exposure, ocular pain associated with generalized neuropathy, traumatic ocular neuropathic pain, ocular pain associated with trigeminal neuralgia, and ocular pain associated with fibromyalgia.

[0072] In some embodiments, the ophthalmic neuropathic pain is at least one selected from the group consisting of corneal neuralgia, conjunctival neuralgia, optic nerve neuralgia, extraocular neuralgia, orbital neuralgia, and palpebral neuralgia.

[0073] In some embodiments, the neuropathic pain is at least one selected from the group consisting of central neuropathic pain and peripheral neuropathic pain.

[0074] In some embodiments, the central neuropathic pain is at least one selected from the group consisting of post-stroke neuropathic pain, syringomyelia pain, neuropathic pain associated with ischemic myelopathy, neuropathic pain associated with compressive myelopathy, neuropathic pain associated with radiation myelopathy, neuropathic pain associated with spinal cord injury, neuropathic pain associated with multiple sclerosis, neuropathic pain associated with Parkinson's disease, phantom limb pain, and neuropathic pain associated with myelitis.

[0075] In some embodiments, the peripheral neuropathic pain is at least one selected from the group consisting of peripheral neuropathic pain associated with metabolic disorders or ischemia, peripheral neuropathic pain associated with infection, peripheral neuropathic pain associated with nerve or nerve root compression, peripheral neuropathic pain associated with chemotherapy, peripheral neuropathic pain associated with radiation therapy, stump pain, peripheral neuropathic pain associated with neuropathy due to tumor compression or infiltration, peripheral neuropathic pain associated with alcoholic polyneuropathy, peripheral neuropathic pain associated with nutritional neuropathy, peripheral neuropathic pain associated with toxic peripheral neuropathy, and peripheral neuropathic pain associated with immune-mediated neuropathy.

[0076] In some embodiments, the peripheral neuropathic pain associated with a metabolic disorder or ischemia is at least one selected from the group consisting of diabetic peripheral neuropathic pain and ischemic peripheral neuropathic pain.

[0077] In some embodiments, the peripheral neuropathic pain associated with an infection is at least one selected from the group consisting of peripheral neuropathic pain associated with a viral infection and peripheral neuropathic pain associated with a spirochete infection.

[0078] In some embodiments, the peripheral neuropathic pain associated with a viral infection is at least one selected from the group consisting of postherpetic neuralgia and peripheral neuropathic pain associated with HIV infection.

[0079] In some embodiments, the peripheral neuropathic pain associated with a spirochete infection is peripheral neuropathic pain associated with a syphilis infection.

[0080] In some embodiments, the peripheral neuropathic pain associated with compression of a nerve or nerve root is at least one selected from the group consisting of sciatica, trigeminal neuralgia, glossopharyngeal neuralgia, neuropathic pain associated with radiculoneuropathy, and neuropathic pain associated with entrapment neuropathy.

[0081] In another aspect, there is provided a method for treating or preventing peripheral neuropathic pain in a subject in need thereof, comprising administering to the subject an effective amount of a polypeptide having at least 70% identity to any one selected from SEQ ID NO: 28, SEQ ID NO: 57, and SEQ ID NOs: 62-74, or a fragment or variant thereof.

[0082] In some embodiments, the polypeptide is the polypeptide of any one of SEQ ID NOs: 28, 57, and 62-74, or a fragment or variant thereof; the polypeptide is the polypeptide of any one of SEQ ID NOs: 28, 57, and 62-74; the polypeptide is the polypeptide of any one of SEQ ID NOs: 28 and 62-74; or the polypeptide is the polypeptide of SEQ ID NO: 28. In some embodiments, the polypeptide is the polypeptide of any one of SEQ ID NOs: 28, 57, and 62-74, or a fragment or variant thereof. In some embodiments, the polypeptide is the polypeptide of any one of SEQ ID NOs: 28, 57, and 62-74. In some embodiments, the polypeptide is the polypeptide of any one of SEQ ID NOs: 28 and 62-74. In some embodiments, the polypeptide is the polypeptide of SEQ ID NO: 28.

[0083] In some embodiments, the peripheral neuropathic pain is at least one selected from the group consisting of peripheral neuropathic pain associated with metabolic disorders or ischemia, peripheral neuropathic pain associated with infection, peripheral neuropathic pain associated with nerve or nerve root compression, peripheral neuropathic pain associated with chemotherapy, peripheral neuropathic pain associated with radiation therapy, stump pain, peripheral neuropathic pain associated with neuropathy due to tumor compression or infiltration, peripheral neuropathic pain associated with alcoholic polyneuropathy, peripheral neuropathic pain associated with nutritional neuropathy, peripheral neuropathic pain associated with toxic peripheral neuropathy, and peripheral neuropathic pain associated with immune-mediated neuropathy.

[0084] In some embodiments, the peripheral neuropathic pain associated with a metabolic disorder or ischemia is at least one selected from the group consisting of diabetic peripheral neuropathic pain and ischemic peripheral neuropathic pain.

[0085] In some embodiments, the peripheral neuropathic pain associated with an infection is at least one selected from the group consisting of peripheral neuropathic pain associated with a viral infection and peripheral neuropathic pain associated with a spirochete infection.

[0086] In some embodiments, the peripheral neuropathic pain associated with a viral infection is at least one selected from the group consisting of postherpetic neuralgia and peripheral neuropathic pain associated with HIV infection.

[0087] In some embodiments, the peripheral neuropathic pain associated with a spirochete infection is peripheral neuropathic pain associated with a syphilis infection.

[0088] In some embodiments, the peripheral neuropathic pain associated with compression of a nerve or nerve root is at least one selected from the group consisting of sciatica, trigeminal neuralgia, glossopharyngeal neuralgia, neuropathic pain associated with radiculoneuropathy, and neuropathic pain associated with entrapment neuropathy.

[0089] In some embodiments, the subject is a mammal. In some embodiments, the subject is any one selected from the group consisting of humans, primates, rodents, dogs, cats, horses, sheep and pigs. In some embodiments, the subject is a pet. In some embodiments, the subject is any one selected from the group consisting of fish, frogs, salamanders, reptiles (e.g., turtles, lizards, snakes and iguanas), birds (e.g., parrots), mice, rats, guinea pigs, gerbils, hamsters, chinchillas, rabbits, ferrets, cats, dogs and pigs.

[0090] In some embodiments, an artificial polypeptide of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a variant of an artificial polypeptide of formula (I), (II), (III), (IV) or (V), or a polypeptide having at least 70% identity to any one selected from SEQ ID NO: 28, SEQ ID NOs: 57, and 62-74, or a fragment or variant thereof, is administered in the form of a formulation comprising the artificial polypeptide of formula (I), (II), (III), (IV), (V), or (VII), or a variant of the artificial polypeptide of formula (I), (II), (III), (IV) or (V), or a polypeptide having at least 70% identity to any one selected from SEQ ID NOs: 28, ...

[0091] In some embodiments, the formulation is in a form suitable for oral administration, hi some embodiments, the formulation is in the form of a tablet, capsule, pill, powder, granule, liquid, suspension, or emulsion.

[0092] In some embodiments, the formulation is in a form suitable for parenteral administration, ie, in the form of a sterile injectable solution, suspension, emulsion, gel (e.g., injectable hydrogel), or sterile powder.

[0093] In some embodiments, the formulation is in a form suitable for topical administration, ie, in the form of a spray, aerosol, inhalable powder, ointment, cream, patch, suppository, paste, film, or gel.

[0094] In some embodiments, the formulation is in the form of a sustained-release, controlled-release, or delayed-release formulation. In some embodiments, the formulation is in the form of a matrix tablet, a compressed tablet with mixed particles having different release rates, an osmotic pump tablet, a sustained- or controlled-release capsule or microcapsule, a sustained- or controlled-release implant, a sustained- or controlled-release granule, a microparticle or microsphere, an enteric-coated capsule or tablet, a colonic placement formulation, a gel (e.g., a hydrogel), a liposomal formulation, an ion-exchange resin formulation, a floating formulation, a bioadhesive formulation, a stimulant-triggered release formulation, and a pulsatile drug delivery system.

[0095] In some embodiments, the formulation is for use in humans.

[0096] In some embodiments, the formulation is a veterinary formulation.

[0097] In another aspect, there is provided an artificial polypeptide of formula (VI) or (VII), or a variant of an artificial polypeptide of (I), (II), (III), (IV) or (V), for use in therapy.

[0098] In another aspect, there is provided an artificial polypeptide of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a variant of an artificial polypeptide of (I), (II), (III), (IV) or (V), for use in treating or preventing pain in a subject in need thereof.

[0099] In another aspect, there is provided a polypeptide having at least 70% identity to any one selected from SEQ ID NO: 28, SEQ ID NO: 57, and 62-74, or a fragment or variant thereof, for use in treating or preventing peripheral neuropathic pain in a subject in need thereof.

[0100] In another aspect, there is provided the use of an artificial polypeptide of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a variant of an artificial polypeptide of (I), (II), (III), (IV) or (V), for the preparation of a medicament for treating or preventing pain in a subject in need thereof.

[0101] In another aspect, there is provided use of a polypeptide having at least 70% identity to any one selected from SEQ ID NO: 28, SEQ ID NO: 57, and SEQ ID NO: 62-74, or a fragment or variant thereof, for the preparation of a medicament for treating or preventing peripheral neuropathic pain in a subject in need thereof.

[0102] In some embodiments, the medicament is for use in humans.

[0103] In some embodiments, the medicine is a veterinary medicine.

[0104]

[0013] Further aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

[0105] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0106] BRIEF DESCRIPTION OF THE DRAWINGS The various features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Brief explanation of the drawings]

[0107] [Figure 1] FIG. 1 shows the 50% PWT values ​​of rats from both the placebo and treatment groups (SEQ ID NOs: 29, 57, 75, 49 and 28, subcutaneous or intravenous, single dose) obtained from the mechanical allodynia studies of Examples 1-3.

[0108] [Figure 2-1]FIG. 2 shows the 50% PWT values ​​of mice from various treatment groups (SEQ ID NOs: 28, 29, 57, 86, 89, 90, 91, 93, 94, 95, 104, 106, 107, 108, 109 and 110, intravenous, single dose) obtained from the mechanical allodynia study in Example 4. [Figure 2-2] FIG. 2 shows the 50% PWT values ​​of mice from various treatment groups (SEQ ID NOs: 28, 29, 57, 86, 89, 90, 91, 93, 94, 95, 104, 106, 107, 108, 109 and 110, intravenous, single dose) obtained from the mechanical allodynia study in Example 4.

[0109] [Figure 3] FIG. 3 shows the 50% PWT values ​​of mice from the sham, vehicle and various treatment groups (SEQ ID NOs: 29, 90 and 93, intravenous, single dose) obtained from the mechanical allodynia test of Example 5.

[0110] [Figure 4] FIG. 4 shows the 50% PWT values ​​of rats from the sham group, model group and treatment group (SEQ ID NO: 29, intravenous, continuous administration) obtained from the mechanical allodynia test in Example 6.

[0111] [Figure 5] FIG. 5 shows the 50% PWT values ​​of mice from the control group, model group, treatment group (once a day) (SEQ ID NO: 29, intraperitoneally, once a day) and treatment group (twice a day) (SEQ ID NO: 29, intraperitoneally, twice a day) obtained from the mechanical allodynia test in Example 7.

[0112] [Figure 6] FIG. 6 shows the number of eye swabs of mice from the control group, model group and test substance group (SEQ ID NO: 29, eye drops, 3 times a day) obtained from the scratching behavior test of Example 8. DETAILED DESCRIPTION OF THE INVENTION

[0113] The patent or application contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Patent Office upon request and payment of the necessary fee.

[0114] Detailed Description definition As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0115] As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures of cells.

[0116] As used herein, the terms "comprise," "include," "contain," and variations thereof are intended to mean open-ended transitional phrases that do not exclude the possibility of additional substances or methods. When such terms are used to describe a particular pharmaceutical composition, formulation, kit, use, or method of the present disclosure, they also encompass situations in which the pharmaceutical composition, formulation, kit, use, or method consists of the listed substances or methods. For example, the phrase "the solvent comprises water" also encompasses situations in which the solvent consists of water, i.e., the solvent contains exclusively water. In the context of the present disclosure, the term "consisting of" is intended to mean a close-ended transitional phrase that excludes the possibility of additional substances or methods.

[0117] As used herein, ranges recited in this disclosure are intended to explicitly disclose each endpoint of the range and each integer subsumed within that range, unless otherwise indicated. For example, "X is a moiety comprising 40 to 65 amino acids" means that the number of amino acids in the X moiety can be 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65. As another example, "Y is a moiety containing 10 to 50 amino acids" means that the number of amino acids in the Y moiety can be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. Furthermore, any subranges consisting of these integers are intended to be encompassed within the scope of the present disclosure. Thus, for example, "X is a moiety containing 40 to 65 amino acids" is considered to expressly disclose subranges such as "X is a moiety containing 41 to 64 amino acids," "X is a moiety containing 42 to 63 amino acids," "X is a moiety containing 43 to 62 amino acids," etc.

[0118] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more standard deviations, in accordance with practice in the art. Alternatively, "about" can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. When particular values ​​are described in this application and claims, unless otherwise specified, the term "about" or "approximately" should be assumed to mean within an acceptable error range for the particular value.

[0119] The term "optionally" means that the subsequently described event of a circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur.

[0120] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymers may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. These terms also encompass amino acid polymers that have been modified by, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component.

[0121] As used herein, the term "fragment," when applied to a protein, refers to a truncated form of a native biologically active protein that may or may not retain at least a portion of its therapeutic and / or biological activity.

[0122] As used herein, the term "variant," when applied to a protein, refers to a protein having sequence homology with a naturally occurring biologically active protein that retains at least a portion of the therapeutic and / or biological activity of the biologically active protein. For example, a variant protein may share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity compared to the reference biologically active protein.

[0123] As used herein, the term "amino acid" refers to any natural and / or unnatural or synthetic amino acid, including, but not limited to, glycine and both the D- and L-optical isomers, as well as amino acid analogs and peptidomimetics. Standard one-letter or three-letter codes are used to designate amino acids.

[0124] The term "naturally occurring L-amino acids" refers to the L optical isomeric forms of glycine (G), proline (P), alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M), cysteine ​​(C), phenylalanine (F), tyrosine (Y), tryptophan (W), histidine (H), lysine (K), arginine (R), glutamine (Q), asparagine (N), glutamic acid (E), aspartic acid (D), serine (S), and threonine (T).

[0125] The terms "hydrophilic" and "hydrophobic" refer to the degree of affinity a substance has for water. Hydrophilic substances have a strong affinity for water and tend to dissolve, mix, or be wetted by water, whereas hydrophobic substances lack substantial affinity for water and tend to repel, not absorb, or not dissolve, mix, or be wetted by water. Amino acids can be characterized based on their hydrophobicity. Examples of "hydrophilic amino acids" are arginine, lysine, threonine, alanine, asparagine, and glutamine. Of particular interest are the hydrophilic amino acids aspartic acid, glutamic acid, serine, and glycine. In some embodiments, "hydrophilic amino acids" refer to arginine, lysine, threonine, alanine, asparagine, glutamine, aspartic acid, glutamic acid, serine, and glycine. Examples of "hydrophobic amino acids" are tryptophan, tyrosine, phenylalanine, methionine, leucine, isoleucine, and valine. In some embodiments, "hydrophobic amino acid" refers to tryptophan, tyrosine, phenylalanine, methionine, leucine, isoleucine, and valine.

[0126] A "host cell" includes an individual cell or cell culture that can be or has been a recipient for a subject vector. A host cell includes the progeny of a single host cell. The progeny may not necessarily be completely identical (in morphology or in genome of total DNA complement) to the original parent cell.

[0127] A "chimeric" protein contains at least one fusion polypeptide containing regions in a position in the sequence that is different from their naturally occurring positions. The regions may normally be in separate proteins and are brought together in the fusion polypeptide, or they may normally be in the same protein but are arranged in a new configuration in the fusion polypeptide. Chimeric proteins can be made, for example, by chemical synthesis, or by creating and translating a polynucleotide in which the peptide regions are encoded in the desired relationship.

[0128] "Conjugated," "linked," "fused," and "fusion" are used interchangeably herein and refer to the joining of two additional chemical elements or components by any means, including chemical conjugation or recombinant means.

[0129] The terms "polynucleotide," "nucleic acid," "nucleotide," and "oligonucleotide" are used interchangeably. The terms "polynucleotide," "nucleic acid," "nucleotide," and "oligonucleotide" refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, multiple loci (single locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. Polynucleotides may contain modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.

[0130] The term "complement of a polynucleotide" refers to a polynucleotide molecule having a complementary base sequence and reverse orientation compared to a reference sequence such that it can hybridize to the reference sequence with complete fidelity.

[0131] The term "recombinant" as applied to a polynucleotide means that the polynucleotide is the product of various combinations of in vitro cloning, restriction and / or ligation steps, and other procedures, resulting in a construct that can potentially be expressed in a host cell.

[0132] The term "homology" or "homologous" refers to the sequence similarity or interchangeability between two or more polynucleotide sequences or two or more polypeptide sequences. When using a program such as BestFit to determine sequence identity, similarity, or homology between two different amino acid sequences, default settings may be used, or an appropriate scoring matrix, such as blosum45 or blosum80, may be selected to optimize the identity, similarity, or homology score. Preferably, homologous polynucleotides are polynucleotides that hybridize under stringent conditions as defined herein and have at least 70%, preferably at least 80%, more preferably at least 90%, more preferably 95%, more preferably 97%, more preferably 98%, and even more preferably 99% sequence identity to their sequences.

[0133] The terms "percent identity" and "% identity," when applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such algorithms may insert gaps in the sequences being compared in a standardized, reproducible manner to optimize the alignment between the two sequences and thus achieve a more meaningful comparison of the two sequences. Percent identity may be measured over the length of the entire defined polynucleotide sequence, as defined, for example, by a particular SEQ ID NO:, or over a shorter length, for example, over the length of a fragment obtained from a larger, defined polynucleotide sequence, for example, a fragment of at least 45, at least 60, at least 90, at least 120, at least 150, at least 210, or at least 450 contiguous residues. It is understood that such lengths are merely exemplary, and that any fragment length supported by the sequences set forth herein in the tables, figures, or sequence listing may be used to describe the length over which percentage identity can be measured.

[0134] "Percent (%) amino acid sequence identity" with respect to a polypeptide sequence identified herein is defined as the percentage of amino acid residues in a query sequence that are identical to the amino acid residues of a second reference polypeptide sequence, or portion thereof, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment to determine percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, and Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms required to achieve maximum alignment over the entire length of the sequences being compared. Percent identity may be measured over the entire length of a defined polypeptide sequence, for example, as defined by a particular SEQ ID NO:, or over a shorter length, for example, over the length of a fragment obtained from a larger defined polypeptide sequence, for example, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70, or at least 150 consecutive residues. It is understood that such lengths are exemplary only, and that any fragment length supported by the sequences shown herein in the tables, figures, or sequence listing can be used to describe the length over which percentage identity can be determined.

[0135] A "vector" is a nucleic acid molecule that transfers an inserted nucleic acid molecule into and / or between host cells, preferably self-replicating in a suitable host. The term encompasses vectors that function primarily for the insertion of DNA or RNA into a cell, replicating vectors that function primarily for the replication of DNA or RNA, and expression vectors that function for the transcription and / or translation of DNA or RNA. Vectors that provide more than one of the above functions are also encompassed. An "expression vector" is a polynucleotide that can be transcribed and translated into polypeptide(s) when introduced into a suitable host cell. An "expression system" usually refers to a suitable host cell comprised of an expression vector that can function to provide a desired expression product.

[0136] As used herein, "t 1 / 2 The term "ln(2) / K el The terminal half-life is calculated as K el is the terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration versus time curve. Half-life typically refers to the time required for half of the amount of an administered substance that has accumulated in an organism to be metabolized or eliminated by normal biological processes. "t 1 / 2 The terms "," "terminal half-life," "elimination half-life," and "circulating half-life" are used interchangeably herein.

[0137] The term "physiological conditions" refers to in vitro conditions, including temperature, salt concentration, and pH, that mimic the range of conditions in a living host as well as those of a living subject. Numerous physiologically relevant conditions have been established for use in in vitro assays. Generally, physiological buffers contain physiological concentrations of salt and are adjusted to a neutral pH ranging from about 6.5 to about 7.8, preferably from about 7.0 to about 7.5. Various physiological buffers are listed in Sambrook et al. (1989). Physiologically relevant temperatures range from about 25°C to about 38°C, preferably from about 35°C to about 37°C.

[0138] The term "antagonist" as used herein includes any molecule that partially or completely blocks, inhibits, or neutralizes the biological activity of the native polypeptide disclosed herein. A method for identifying a polypeptide antagonist may include contacting the native polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the native polypeptide. In the context of this disclosure, antagonists may include proteins, nucleic acids, carbohydrates, antibodies, or any other molecules that reduce the effect of biologically active proteins.

[0139] The term "agonist" is used in the broadest sense and includes any molecule that mimics the biological activity of a native polypeptide disclosed herein. Suitable agonist molecules specifically include agonist antibodies or antibody fragments, fragments or amino acid sequence variants of native polypeptides, peptides, small organic molecules, and the like. Methods for identifying agonists of a native polypeptide can include contacting the native polypeptide with a candidate agonist molecule and measuring a detectable change in one or more biological activities normally associated with the native polypeptide.

[0140] For purposes herein, the term "activity" refers to an action or effect of a component of a fusion protein that corresponds to that of the corresponding native biologically active protein, and "biological activity" refers to an in vitro or in vivo biological function or effect, including, but not limited to, receptor binding, antagonist activity, agonist activity, or cellular or physiological response.

[0141] As used herein, "treatment" or "treating," "alleviating," and "relieving" are used interchangeably. These terms refer to an approach to achieving beneficial or desired results, including, but not limited to, therapeutic benefit and / or preventative benefit. "Therapeutic benefit" refers to the eradication or reduction of the underlying disorder being treated. Therapeutic benefit is also achieved by eradicating or reducing one or more physiological symptoms associated with the underlying disease state, such that an improvement is observed in the subject, although the subject may still suffer from the underlying disorder. For preventative benefit, the composition may be administered to a subject at risk of developing a particular disease state, or to a subject who reports one or more physiological symptoms of the disease, even if the disease may not have been diagnosed.

[0142] The term "therapeutic effect" refers to a physiological effect caused by a polypeptide of the present disclosure, including, but not limited to, curing, reducing, alleviating, or preventing a disease state in a human or other animal, or otherwise enhancing the physical or mental well-being of a human or animal. Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0143] The term "effective amount" refers to an amount of a biologically active protein, alone or as part of a fusion protein composition, that, when administered to a subject in one or multiple doses, can have any detectable beneficial effect on any symptom, aspect, measured parameter, or characteristic of a disease state or condition. Such an effect need not be absolute to be beneficial. A disease state can refer to a disorder or disease.

[0144] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, formulations, or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and other animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0145] The terms "formulation" and "dosage form" are used interchangeably and refer to a pharmaceutical composition that is formulated according to clinical requirements in a form that can be administered directly to a subject in need thereof for prophylactic or therapeutic use.

[0146] The term "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, carrier, or vehicle used for preparing a formulation or dosage form according to the present disclosure. Each excipient must be "acceptable" in the sense of being compatible with the other ingredients of the formulation or dosage form and not injurious to the patient.

[0147] As used herein, the terms "subject," "individual," or "patient" refer to any animal that can be used with the present disclosure, including, but not limited to, humans, primates, rodents, dogs, cats, horses, sheep, pigs, etc.

[0148] The terms "administer," "administered," "administers," "administering," and "dosing" are used interchangeably and are defined as providing a compound, composition, formulation, and / or dosage form according to the present disclosure to a subject in need thereof via routes known in the art, including, but not limited to, oral, buccal, topical, transmucosal, transdermal, rectal, and parenteral routes of administration. In some embodiments, an oral route of administration is used. In some embodiments, a parenteral route of administration is used, including intravenous, intraarterial, intramuscular, subcutaneous, intraosseous, and intraperitoneal. In some embodiments, a topical route of administration is used.

[0149] As used herein, the term "in vivo" refers to events that take place inside a subject's body.

[0150] As used herein, the term "in vitro" refers to an event that occurs outside of a subject's body. In some embodiments, an in vitro assay encompasses any assay that is performed outside of a subject's body. An in vitro assay encompasses cell-based assays in which live or dead cells are used. An in vitro assay also encompasses cell-free assays in which no intact cells are used.

[0151] As used herein, the term "pain" refers to an unpleasant sensory and emotional experience associated with, or similar to, actual or potential tissue damage. In the context of this disclosure, the term "pain" is intended to include all types of acute pain, chronic pain (e.g., nociceptive pain, neuropathic pain, and mixed pain), and transitional pain.

[0152] The terms "neuropathic pain" and "neuralgia" are used interchangeably herein and refer to pain caused by a lesion or disease in the body's somatosensory nervous system. The term "neuropathic pain" can be further divided into central neuropathic pain and peripheral neuropathic pain depending on the location of the lesion or disease. In some embodiments, the neuropathic pain is peripheral neuropathic pain. In the context of the present disclosure, peripheral neuropathic pain of particular interest includes, but is not limited to, peripheral neuropathic pain associated with metabolic disorders or ischemia, such as diabetic peripheral neuropathic pain or ischemic peripheral neuropathic pain; peripheral neuropathic pain associated with viral infection, such as postherpetic neuralgia; and peripheral neuropathic pain associated with compression of a nerve or nerve root, such as sciatica.

[0153] As used herein, the term "mixed pain" refers to a pain state having characteristics of nociceptive pain and neuropathic pain. Examples of mixed pain include, but are not limited to, arthritis pain, back pain, cancer pain, dental pain, fibromyalgia, chronic inflammatory pain, lower back pain, neck pain, and eye pain. In the context of this disclosure, mixed pain of particular interest includes, but is not limited to, gout pain, cancer pain, and eye pain. Gout is a common and complex form of arthritis characterized by sudden (often nocturnal) severe attacks of pain (most often in the big toe), in addition to swelling, redness, and tenderness in one or more joints. Cancer pain can result from tumors compressing or infiltrating nearby body parts (i.e., tumor-related cancer pain), diagnostic and / or therapeutic procedures, or other changes in the skin, bones, nerves, and other conditions caused by hormonal imbalances, infections, or immune responses. In some embodiments, the cancer pain is tumor-related cancer pain, such as cancer-related nerve pain, cancer-related bone pain, cancer-related soft tissue pain, and cancer-related referred pain. In some embodiments, the cancer pain is cancer pain associated with diagnostic and / or therapeutic procedures, such as cancer-related phantom pain and chemotherapy-related cancer pain. In some embodiments, the chemotherapy-related cancer pain is cancer pain associated with chemotherapy-induced peripheral neuropathy (CIPN). In some embodiments, the chemotherapy is administered by administering a cytotoxic agent to a subject in need thereof. In some embodiments, the cancer pain is cancer-related bone pain, such as bone pain associated with bone cancer (e.g., chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma of bone, osteosarcoma, and fibrochondromesenchymoma of bone) and bone metastatic tumors. In some embodiments, the cancer pain is cancer pain associated with chemotherapy-induced peripheral neuropathy, such as cancer pain associated with platinum anticancer drug-induced peripheral neuropathy. Eye pain can be described as a sharp, aching or throbbing pain in one or both eyes.In some embodiments, the ocular pain is at least one selected from the group consisting of ocular nociceptive pain and ocular neuropathic pain.Ocular nociceptive pain is often caused by various injuries on the front of the eye, such as injury, surgery, contact lenses, and foreign bodies.In contrast, ocular neuropathic pain refers to the heightened sensation of ocular pain in response to normally non-painful stimuli, and is often caused by factors such as allergy, infection, inflammation, chronic ocular surface disease, surgery, toxic keratopathy, radiation, ultraviolet light exposure, systemic neuropathy, trauma, trigeminal neuralgia, and fibromyalgia.Ocular neuropathic pain can occur in different parts of the eye, including but not limited to the cornea, conjunctiva, optic nerve, extraocular muscles, orbit, and eyelid.Therefore, ocular neuropathic pain can be in the form of corneal neuralgia, conjunctival neuralgia, optic nerve neuralgia, extraocular muscle neuralgia, orbital neuralgia, or palpebral neuralgia.

[0154] The terms "cancer" and "malignancy" are used interchangeably herein to refer to a group of hyperproliferative diseases characterized by uncontrolled, abnormal cell growth and the potential to invade or spread to other parts of the body. In the context of this disclosure, the term "cancer" includes all types of malignancies, including carcinomas (i.e., cancers derived from epithelial cells), lymphomas and leukemias (i.e., cancers arising from hematopoietic cells that tend to leave the bone marrow and mature in the lymph nodes and blood, respectively), sarcomas (i.e., cancers arising from connective tissue), blastomas (i.e., cancers derived from immature precursor cells or embryonic tissue), and germ cell tumors (i.e., cancers derived from pluripotent cells). Examples of cancers include cancers of the bone and muscle (e.g., chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma of bone, osteosarcoma, rhabdomyosarcoma, leiomyosarcoma, myxosarcoma, and fibrochondromesymoma of bone), cancers of the brain and nervous system (e.g., astrocytoma, brain stem glioma, pilocytic astrocytoma, ependymoma, primitive neuroectodermal tumor, cerebellar astrocytoma, cerebral astrocytoma, glioblastoma, glioma, medulloblastoma, neuroblastoma, oligodendroglioma, glioma, medulloblastoma, neuroblastoma, gli ... tumors, pineal astrocytoma, pituitary adenoma, visual pathway and hypothalamic glioma), cancers of the breast (e.g., inflammatory breast cancer, invasive lobular carcinoma, tubular carcinoma, invasive cribriform carcinoma, medullary carcinoma, phyllodes tumor, secretory carcinoma of the breast and papillary carcinoma of the breast), cancers of the endocrine system (e.g., adrenocortical carcinoma, islet cell carcinoma of the pancreas, multiple endocrine neoplasia syndrome, parathyroid carcinoma, pheochromocytoma, thyroid carcinoma and Merkel cell carcinoma), cancers of the eye (e.g., uveal melanoma, retinoblastoma and optic nerve glioma), gastrointestinal cancers (e.g., anal cancer, appendix cancer, cholangiocarcinoma, gastrointestinal carcinoid tumors, colon cancer, extrahepatic bile duct cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal stromal tumors, hepatocellular carcinoma, pancreatic cancer, rectal cancer, and small intestine cancer), genitourinary and gynecological cancers (e.g., bladder cancer, cervical cancer, endometrial cancer, extragonadal germ cell tumors, ovarian cancer) , ovarian germ cell tumor, penile cancer, kidney cancer, renal cell carcinoma, transitional cell carcinoma, prostate cancer, testicular cancer, gestational trophoblastic tumor, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer and nephroblastoma), head and neck cancer (e.g., esophageal cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, oropharynx cancer, paranasal sinus and nasal cavity cancer, pharyngeal cancer, salivary gland cancer and hypopharyngeal cancer), hematopoietic cancer (e.g., acute biphenotypic leukemia, acute eosinophilic leukemia,Leukemias such as acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid dendritic cell leukemia, B-cell prolymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphocytic leukemia, mast cell leukemia, precursor B-lymphoblastic leukemia and T-cell prolymphocytic leukemia, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, intravascular large B-cell lymphoma, lymphoplasmacytic lymphoma, lymphomatoid granulomatosis, mantle cell lymphoma, marginal zone B-cell lymphoma, mediastinal large B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, mycosis fungoides, nodal marginal zone lymphoma lymphomas such as B-cell lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, primary cutaneous follicular lymphoma, primary cutaneous immunocytoma, primary effusion lymphoma, plasmablastic lymphoma, Sézary syndrome and splenic marginal zone lymphoma, and multiple myeloma and myelodysplastic syndromes), cancers of the skin (e.g., basal cell carcinoma, squamous cell carcinoma, squamous cell skin cancer, cutaneous adnexal tumors, melanoma, Merkel cell carcinoma, keratoacanthoma and sarcomas of primary cutaneous origin), cancers of the thoracic and respiratory tract (e.g., bronchial adenoma, mesothelioma, pleuropulmonary blastoma, laryngeal carcinoma, thymic carcinoma, thymoma, and lung cancers such as adenocarcinoma of the lung, small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma of the lung), Kaposi's sarcoma, liposarcoma, desmoplastic small round cell tumor and epithelioid hemangioendothelioma. In the context of this disclosure, the term "cancer" is intended to encompass both primary cancers and metastatic tumors derived therefrom (e.g., bone metastatic tumors). Furthermore, the term "cancer" is also intended to encompass early-stage, intermediate-stage, and advanced cancers, including any metastatic, unresectable, recurrent, or incurable cancer.

[0155] The term "cytotoxic agent," as used herein, refers to a substance that kills cells, especially cancer cells. These agents can stop cancer cells from dividing and growing, and can reduce tumor size.

[0156] As used herein, the term "related to" refers to "caused by." For example, "pain related to acute injury" means pain caused by acute injury, i.e., pain in which acute injury plays at least a role. Analgesic Polypeptides

[0157] In one aspect, an artificial polypeptide of formula XY(VI) is provided.

[0158] In some embodiments, X of formula (VI) comprises a sequence having at least 70% identity to SEQ ID NO:1. In some embodiments, X of formula (VI) comprises a sequence having at least 75% identity to SEQ ID NO:1. In some embodiments, X of formula (VI) comprises a sequence having at least 80% identity to SEQ ID NO:1. In some embodiments, X of formula (VI) comprises a sequence having at least 85% identity to SEQ ID NO:1. In some embodiments, X of formula (VI) comprises a sequence having at least 90% identity to SEQ ID NO:1. In some embodiments, X of formula (VI) comprises a sequence having at least 95% identity to SEQ ID NO:1. In some embodiments, X of formula (VI) comprises a sequence having at most 95% identity to SEQ ID NO:1. In some embodiments, X of formula (VI) comprises a sequence having at most 90% identity to SEQ ID NO:1. In some embodiments, X of formula (VI) comprises a sequence having at most 85% identity to SEQ ID NO:1. In some embodiments, X of formula (VI) comprises a sequence having at most 80% identity to SEQ ID NO: 1. In some embodiments, X of formula (VI) comprises a sequence having at most 75% identity to SEQ ID NO: 1.

[0159] In some embodiments, Y of formula (VI) is a moiety comprising a sequence having at least 70% identity to SEQ ID NO:2. In some embodiments, Y of formula (VI) is a moiety comprising a sequence having at least 75% identity to SEQ ID NO:2. In some embodiments, Y of formula (VI) is a moiety comprising a sequence having at least 80% identity to SEQ ID NO:2. In some embodiments, Y of formula (VI) is a moiety comprising a sequence having at least 85% identity to SEQ ID NO:2. In some embodiments, Y of formula (VI) is a moiety comprising a sequence having at least 90% identity to SEQ ID NO:2. In some embodiments, Y of formula (VI) is a moiety comprising a sequence having at least 95% identity to SEQ ID NO:2. In some embodiments, Y of formula (VI) is a moiety comprising a sequence having at most 95% identity to SEQ ID NO:2. In some embodiments, Y of formula (VI) is a sequence having at most 90% identity to SEQ ID NO:2. In some embodiments, Y of formula (VI) is a sequence having at most 85% identity to SEQ ID NO:2. In some embodiments, Y of formula (VI) comprises a sequence having at most 80% identity to SEQ ID NO: 2. In some embodiments, Y of formula (VI) comprises a sequence having at most 75% identity to SEQ ID NO: 2.

[0160] In some embodiments, Y in formula (VI) is a hydrophobic moiety, and at least 50% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (VI) is a hydrophobic moiety, and at least 55% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (VI) is a hydrophobic moiety, and at least 60% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (VI) is a hydrophobic moiety, and at least 65% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (VI) is a hydrophobic moiety, and at least 70% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (VI) is a hydrophobic moiety, and at least 75% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y of formula (VI) is a hydrophobic moiety, and at least 80% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y of formula (VI) is a hydrophobic moiety, and at least 85% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y of formula (VI) is a hydrophobic moiety, and at least 90% of the amino acids of Y are selected from I, V, L, F, C, M, and A.

[0161] In some embodiments, X in formula (VI) is a moiety containing 40-65 amino acids, and the total number of R, K, T, A, N, Q, D, E, S, and G in X is greater than 30. In some embodiments, X in formula (VI) is a moiety containing 40-65 amino acids, and the total number of R, K, T, A, N, Q, D, E, S, and G in X is 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. In some embodiments, X in formula (VI) is a moiety containing 40-65 amino acids, and the total number of W, Y, F, M, L, I, and V in X is 20 or less. In some embodiments, X in formula (VI) is a moiety containing 40-65 amino acids, and the total number of W, Y, F, M, L, I, and V in X is 19, 18, 17, 16, 15, or 14.

[0162] In some embodiments, Y in formula (VI) is a moiety comprising 10 to 50 amino acids, and the total number of R, K, T, A, N, Q, D, E, S, and G in Y is greater than 10. In some embodiments, Y in formula (VI) is a moiety comprising 10 to 50 amino acids, and the total number of R, K, T, A, N, Q, D, E, S, and G in Y is 11, 12, 13, 14, or 15. In some embodiments, Y in formula (VI) is a moiety comprising 10 to 50 amino acids, and the total number of W, Y, F, M, L, I, and V in X is 20 or less. In some embodiments, Y in formula (VI) is a moiety comprising 10 to 50 amino acids, and the total number of W, Y, F, M, L, I, and V in Y is 19, 18, 17, 16, 15, or 14.

[0163] In some embodiments, X in formula (VI) comprises a sequence having at least 70% identity to any one selected from SEQ ID NOs: 80-83. In some embodiments, X in formula (VI) comprises a sequence having at least 75% identity to any one selected from SEQ ID NOs: 80-83. In some embodiments, X in formula (VI) comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 80-83. In some embodiments, X in formula (VI) comprises a sequence having at least 85% identity to any one selected from SEQ ID NOs: 80-83. In some embodiments, X in formula (VI) comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 80-83. In some embodiments, X in formula (VI) comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 80-83. In some embodiments, X of formula (VI) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 80 to 83. In some embodiments, X of formula (VI) comprises any one sequence selected from SEQ ID NOs: 80 to 83. In some embodiments, X of formula (VI) is any one sequence selected from SEQ ID NOs: 80 to 83.

[0164] In some embodiments, Y of formula (VI) comprises a sequence having at least 70% identity to SEQ ID NO:3. In some embodiments, Y of formula (VI) comprises a sequence having at least 75% identity to SEQ ID NO:3. In some embodiments, Y of formula (VI) comprises a sequence having at least 80% identity to SEQ ID NO:3. In some embodiments, Y of formula (VI) comprises a sequence having at least 85% identity to SEQ ID NO:3. In some embodiments, Y of formula (VI) comprises a sequence having at least 90% identity to SEQ ID NO:3. In some embodiments, Y of formula (VI) comprises a sequence having at least 95% identity to SEQ ID NO:3. In some embodiments, Y of formula (VI) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO:3. In some embodiments, Y of formula (VI) comprises the sequence of SEQ ID NO:3. In some embodiments, Y of formula (VI) is the sequence of SEQ ID NO:3.

[0165] In some embodiments, an artificial polypeptide of Formula (VI) comprises a sequence at least 70% identical to any one of SEQ ID NOs: 90-93. In some embodiments, an artificial polypeptide of Formula (VI) comprises a sequence at least 75% identical to any one of SEQ ID NOs: 90-93. In some embodiments, an artificial polypeptide of Formula (VI) comprises a sequence at least 80% identical to any one of SEQ ID NOs: 90-93. In some embodiments, an artificial polypeptide of Formula (VI) comprises a sequence at least 85% identical to any one of SEQ ID NOs: 90-93. In some embodiments, an artificial polypeptide of Formula (VI) comprises a sequence at least 90% identical to any one of SEQ ID NOs: 90-93. In some embodiments, an artificial polypeptide of Formula (VI) comprises a sequence at least 95% identical to any one of SEQ ID NOs: 90-93. In some embodiments, an artificial polypeptide of Formula (VI) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of SEQ ID NOs: 90-93. In some embodiments, an artificial polypeptide of Formula (VI) comprises a sequence that is any one of SEQ ID NOs: 90-93. In some embodiments, an artificial polypeptide of Formula (VI) is a sequence that is any one of SEQ ID NOs: 90-93.

[0166] In one aspect, an artificial polypeptide of formula XY(VII) is provided.

[0167] In some embodiments, X is a portion comprising a variant of the sequence of SEQ ID NO: 1, wherein the variant has at least 1, 2, 3, 4, or 5 amino acid insertions relative to SEQ ID NO: 1. In some embodiments, X is a portion comprising a variant of the sequence of SEQ ID NO: 1, wherein the variant has at least 1 amino acid insertion relative to SEQ ID NO: 1. In some embodiments, X is a portion comprising a variant of the sequence of SEQ ID NO: 1, wherein the variant has at least 1 amino acid insertion relative to SEQ ID NO: 1. In some embodiments, X is a portion comprising a variant of the sequence of SEQ ID NO: 1, wherein the variant has at least 2 amino acid insertions relative to SEQ ID NO: 1. In some embodiments, X is a portion comprising a variant of the sequence of SEQ ID NO: 1, wherein the variant has at least 2 amino acid insertions relative to SEQ ID NO: 1. In some embodiments, X is a portion comprising a variant of the sequence of SEQ ID NO: 1, wherein the variant has at least 3 ...4 amino acid insertions relative to SEQ ID NO: 1. In some embodiments, X is a portion comprising a variant of the sequence of SEQ ID NO: 1, wherein the variant is characterized by having a 4 amino acid insertion relative to SEQ ID NO: 1. In some embodiments, X is a portion comprising a variant of the sequence of SEQ ID NO: 1, wherein the variant is characterized by having at least a 5 amino acid insertion relative to SEQ ID NO: 1. In some embodiments, X is a portion comprising a variant of the sequence of SEQ ID NO: 1, wherein the variant is characterized by having a 5 amino acid insertion relative to SEQ ID NO: 1.

[0168] In some embodiments, at least 20% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 25% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 30% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 35% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 40% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 45% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 50% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 55% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 60% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 65% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 70% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 75% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 80% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 85% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 90% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H.

[0169] In some embodiments, Y is a moiety comprising 10 to 30 amino acids. In some embodiments, Y is a moiety comprising 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids, or 30 amino acids. In some embodiments, Y is a moiety comprising 11 to 29 amino acids. In some embodiments, Y is a moiety comprising 12 to 28 amino acids. In some embodiments, Y is a moiety comprising 13 to 27 amino acids. In some embodiments, Y is a moiety comprising 14 to 26 amino acids. In some embodiments, Y is a moiety comprising 15 to 25 amino acids. In some embodiments, Y is a moiety comprising 15 to 25 amino acids. In some embodiments, Y is a moiety comprising 18 to 25 amino acids. In some embodiments, Y is a moiety comprising 20 to 25 amino acids.

[0170] In some embodiments, Y comprises a sequence having at least 15 consecutive AAs of SEQ ID NO:2. In some embodiments, Y comprises a sequence having 15 consecutive AAs of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 16 consecutive AAs of SEQ ID NO:2. In some embodiments, Y comprises a sequence having 16 consecutive AAs of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 17 consecutive AAs of SEQ ID NO:2. In some embodiments, Y comprises a sequence having 17 consecutive AAs of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 18 consecutive AAs of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 18 consecutive AAs of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 19 consecutive AAs of SEQ ID NO:2. In some embodiments, Y comprises a sequence having 19 consecutive AAs of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 20 consecutive AAs of SEQ ID NO:2. In some embodiments, Y comprises a sequence having 20 consecutive AAs of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 21 consecutive AA of SEQ ID NO:2. In some embodiments, Y comprises a sequence having 21 consecutive AA of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 22 consecutive AA of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 22 consecutive AA of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 23 consecutive AA of SEQ ID NO:2. In some embodiments, Y comprises a sequence having 23 consecutive AA of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 24 consecutive AA of SEQ ID NO:2. In some embodiments, Y comprises a sequence having 24 consecutive AA of SEQ ID NO:2. In some embodiments, Y comprises a sequence having at least 25 consecutive AA of SEQ ID NO:2. In some embodiments, Y comprises a sequence having 25 consecutive AA of SEQ ID NO:2.

[0171] In some embodiments, Y, is a moiety comprising a variant of the sequence of SEQ ID NO: 2, wherein the variant is characterized by having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids truncated relative to SEQ ID NO: 2. In some embodiments, the at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids truncated relative to SEQ ID NO: 2. In some embodiments, the at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids truncated relative to SEQ ID NO: 2. In some embodiments, the 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid truncation is located at the C-terminus of Y.

[0172] In some embodiments, the total number of E or D in X is at least 8. In some embodiments, the total number of E or D in X is 8. In some embodiments, the total number of E or D in X is at least 9. In some embodiments, the total number of E or D in X is 9. In some embodiments, the total number of E or D in X is at least 10. In some embodiments, the total number of E or D in X is 10. In some embodiments, the total number of E or D in X is at least 11. In some embodiments, the total number of E or D in X is 11. In some embodiments, the total number of E or D in X is at least 12. In some embodiments, the total number of E or D in X is 12. In some embodiments, the total number of E or D in X is at most 15. In some embodiments, the total number of E or D in X is 15. In some embodiments, the total number of E or D in X is at most 14. In some embodiments, the total number of E or D in X is 14. In some embodiments, the total number of E or D in X is at most 13. In some embodiments, the total number of E or D in X is 13. In some embodiments, the total number of E or D in X is up to 12. In some embodiments, the total number of E or D in X is 12. In some embodiments, the total number of E or D in X is up to 11. In some embodiments, the total number of E or D in X is 11. In some embodiments, the total number of E or D in X is up to 10. In some embodiments, the total number of E or D in X is 10.

[0173] In some embodiments, X in formula (VII) is a moiety containing 40-65 amino acids, and the total number of R, K, T, A, N, Q, D, E, S, and G in X is greater than 30. In some embodiments, X in formula (VII) is a moiety containing 40-65 amino acids, and the total number of R, K, T, A, N, Q, D, E, S, and G in X is 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. In some embodiments, X in formula (VII) is a moiety containing 40-65 amino acids, and the total number of W, Y, F, M, L, I, and V in X is 20 or less. In some embodiments, X in formula (VII) is a moiety containing 40-65 amino acids, and the total number of W, Y, F, M, L, I, and V in X is 19, 18, 17, 16, 15, or 14.

[0174] In some embodiments, 40-65% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, at least 40% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, at least 45% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, at least 50% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, at least 55% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, at least 60% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, up to 65% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, up to 60% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, up to 55% of the amino acids of Y are selected from I, V, L, F, C, M and A. In some embodiments, up to 50% of the amino acids of Y are selected from I, V, L, F, C, M and A. In some embodiments, up to 45% of the amino acids of Y are selected from I, V, L, F, C, M and A.

[0175] In some embodiments, the total number of R, K, T, A, N, Q, D, E, S, and G in Y is 10 or less. In some embodiments, the total number of R, K, T, A, N, Q, D, E, S, and G in Y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the total number of W, Y, F, M, L, I, and V in Y is 15 or less. In some embodiments, the total number of W, Y, F, M, L, I, and V in Y is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0176] In some embodiments, X of Formula (VII) comprises a sequence having at least 70% identity to SEQ ID NO: 96. In some embodiments, X of Formula (VII) comprises a sequence having at least 75% identity to SEQ ID NO: 96. In some embodiments, X of Formula (VII) comprises a sequence having at least 80% identity to SEQ ID NO: 96. In some embodiments, X of Formula (VII) comprises a sequence having at least 85% identity to SEQ ID NO: 96. In some embodiments, X of Formula (VII) comprises a sequence having at least 90% identity to SEQ ID NO: 96. In some embodiments, X of Formula (VII) comprises a sequence having at least 95% identity to SEQ ID NO: 96. In some embodiments, X of Formula (VII) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO: 96. In some embodiments, X of Formula (VII) comprises the sequence of SEQ ID NO: 96. In some embodiments, X of Formula (VII) is the sequence of SEQ ID NO: 96.

[0177] In some embodiments, Y in formula (VII) comprises a sequence having at least 70% identity to any one selected from SEQ ID NOs: 97-103. In some embodiments, Y in formula (VII) comprises a sequence having at least 75% identity to any one selected from SEQ ID NOs: 97-103. In some embodiments, Y in formula (VII) comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 97-103. In some embodiments, Y in formula (VII) comprises a sequence having at least 85% identity to any one selected from SEQ ID NOs: 97-103. In some embodiments, Y in formula (VII) comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 97-103. In some embodiments, Y in formula (VII) comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 97-103. In some embodiments, Y of formula (VII) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 97 to 103. In some embodiments, Y of formula (VII) comprises a sequence that is any one selected from SEQ ID NOs: 97 to 103. In some embodiments, Y of formula (VII) is a sequence that is any one selected from SEQ ID NOs: 97 to 103.

[0178] In some embodiments, an engineered polypeptide of Formula (VII) comprises a sequence at least 70% identical to any one of SEQ ID NOs: 104-110. In some embodiments, an engineered polypeptide of Formula (VII) comprises a sequence at least 75% identical to any one of SEQ ID NOs: 104-110. In some embodiments, an engineered polypeptide of Formula (VII) comprises a sequence at least 80% identical to any one of SEQ ID NOs: 104-110. In some embodiments, an engineered polypeptide of Formula (VII) comprises a sequence at least 85% identical to any one of SEQ ID NOs: 104-110. In some embodiments, an engineered polypeptide of Formula (VII) comprises a sequence at least 90% identical to any one of SEQ ID NOs: 104-110. In some embodiments, an engineered polypeptide of Formula (VII) comprises a sequence at least 95% identical to any one of SEQ ID NOs: 104-110. In some embodiments, an artificial polypeptide of Formula (VII) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 104-110. In some embodiments, an artificial polypeptide of Formula (VII) comprises a sequence selected from SEQ ID NOs: 104-110. In some embodiments, an artificial polypeptide of Formula (VII) is a sequence selected from SEQ ID NOs: 104-110.

[0179] In another aspect, variants of the artificial polypeptides of formula (I) are provided.

[0180] In some embodiments, at least 20% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 25% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 30% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 35% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 40% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 45% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 50% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 55% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 60% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 65% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 70% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 75% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 80% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 85% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 90% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H.

[0181] In some embodiments, X in the variant comprises a sequence having at least 70% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 75% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 80% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 85% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 90% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 95% identity to SEQ ID NO:1.

[0182] In some embodiments, Y in the variant may be a moiety comprising 10 to 50 amino acids, and the total number of cysteines (C) in Y is 5. In some embodiments, Y in the variant may be a moiety comprising 10 to 50 amino acids, and the total number of cysteines (C) in Y is less than 5. In some embodiments, Y in the variant may be a moiety comprising 10 to 50 amino acids, and the total number of cysteines (C) in Y is 4. In some embodiments, Y in the variant may be a moiety comprising 10 to 50 amino acids, and the total number of cysteines (C) in Y is less than 4. In some embodiments, Y in the variant may be a moiety comprising 10 to 50 amino acids, and the total number of cysteines (C) in Y is 3. In some embodiments, Y in the variant may be a moiety comprising 10 to 50 amino acids, and the total number of cysteines (C) in Y is less than 3. In some embodiments, Y in the variant may be a moiety comprising 10 to 50 amino acids, and the total number of cysteines (C) in Y is 2. In some embodiments, Y in the variant may be a moiety comprising 10-50 amino acids, wherein the total number of cysteines (C) in Y is less than 2. In some embodiments, Y in the variant may be a moiety comprising 10-50 amino acids, wherein the total number of cysteines (C) in Y is 1. In some embodiments, Y in the variant may be a moiety comprising 10-50 amino acids, wherein the total number of cysteines (C) in Y is less than 1. In some embodiments, Y in the variant may be a moiety comprising 10-50 amino acids, wherein the total number of cysteines (C) in Y is 0.

[0183] In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 8. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 9. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 10. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 11. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 12. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 13. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 14. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 15.

[0184] In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 5. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 5 or less. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 4. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 4 or less. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 3. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 3 or less. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 2. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 2 or less. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 1. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 1 or less.

[0185] In some embodiments, Y in the variant comprises a sequence having at least 70% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments, Y in the variant comprises a sequence having at least 75% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments, Y in the variant comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments, Y in the variant comprises a sequence having at least 85% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments, Y in the variant comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments, Y in the variant comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments, Y in the variant comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments, Y in the variant comprises any one sequence selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments, Y in the variant is any one sequence selected from SEQ ID NOs: 3-15, 58-61, and 84-85.

[0186] In some embodiments, Y in the variant comprises a sequence having at least 70% identity to any one selected from SEQ ID NOs: 3-18, 58-61, and 84-85. In some embodiments, Y in the variant comprises a sequence having at least 75% identity to any one selected from SEQ ID NOs: 3-18, 58-61, and 84-85. In some embodiments, Y in the variant comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 3-18, 58-61, and 84-85. In some embodiments, Y in the variant comprises a sequence having at least 85% identity to any one selected from SEQ ID NOs: 3-18, 58-61, and 84-85. In some embodiments, Y in the variant comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-18, 58-61, and 84-85. In some embodiments, Y in the variant comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 3-18, 58-61, and 84-85. In some embodiments, Y in the variant comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 3-18, 58-61, and 84-85. In some embodiments, Y in the variant comprises any one sequence selected from SEQ ID NOs: 3-18, 58-61, and 84-85. In some embodiments, Y in the variant is any one sequence selected from SEQ ID NOs: 3-18, 58-61, and 84-85.

[0187] In another aspect, variants of the artificial polypeptide of formula (II) are provided.

[0188] In some embodiments, at least 20% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 25% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 30% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 35% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 40% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 45% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 50% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 55% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 60% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 65% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 70% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 75% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 80% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 85% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 90% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H.

[0189] In some embodiments, X in the variant comprises a sequence having at least 70% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 75% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 80% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 85% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 90% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 95% identity to SEQ ID NO:1.

[0190] In some embodiments, Y in the variant comprises a sequence that has at most 50% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 55% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 60% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 65% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 70% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 75% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 80% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 85% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 90% identity to SEQ ID NO:2.

[0191] In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 8. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 9. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 10. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 11. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 12. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 13. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 14. In some embodiments, the total number of hydrophobic amino acids in Y, in the variants is greater than 15.

[0192] In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 5. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 5 or less. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 4. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 4 or less. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 3. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 3 or less. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 2. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 2 or less. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 1. In some embodiments, the total number of hydrophilic amino acids in Y, in the variant is 1 or less.

[0193] In some embodiments, Y in the variant comprises a sequence having at least 70% identity to any one selected from SEQ ID NOs: 16-18. In some embodiments, Y in the variant comprises a sequence having at least 75% identity to any one selected from SEQ ID NOs: 16-18. In some embodiments, Y in the variant comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 16-18. In some embodiments, Y in the variant comprises a sequence having at least 85% identity to any one selected from SEQ ID NOs: 16-18. In some embodiments, Y in the variant comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 16-18. In some embodiments, Y in the variant comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 16-18. In some embodiments, Y in the variant comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 16-18. In some embodiments, Y in the variant comprises any one of the sequences selected from SEQ ID NOs: 16 to 18. In some embodiments, Y in the variant is any one of the sequences selected from SEQ ID NOs: 16 to 18.

[0194] In another aspect, variants of the artificial polypeptide of formula (III) are provided.

[0195] In some embodiments, at least 20% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 25% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 30% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 35% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 40% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 45% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 50% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 55% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 60% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 65% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 70% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 75% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 80% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 85% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 90% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H.

[0196] In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 33. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 32. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 31. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 30. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 29. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 28. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 27. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 26. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 25. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 24. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 23. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 22. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 21. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 20.

[0197] In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 10. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 11. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 12. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 13. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 14. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 15. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 16. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 17. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 18. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 19. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 20. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 21. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 22. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 23. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of hydrophilic amino acids in X is greater than 24. In some embodiments, X in the variant is a moiety comprising 40-65 amino acids, and the total number of hydrophilic amino acids in X is greater than 25.

[0198] In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 15 or less. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 14 or less. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 13 or less. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 12 or less. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 11 or less. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 10 or less. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 5 or less.

[0199] In some embodiments, X in the variant comprises a sequence having at least 70% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 75% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 80% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 85% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 90% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 95% identity to SEQ ID NO:1.

[0200] In some embodiments, Y in the variant is a moiety comprising a sequence having at least 70% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising a sequence having at least 75% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising a sequence having at least 80% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising a sequence having at least 85% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising a sequence having at least 90% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising a sequence having at least 95% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising the sequence of SEQ ID NO:2. In some embodiments, Y in the variant is a moiety which is the sequence of SEQ ID NO:2.

[0201] In some embodiments, Y in the variant is a hydrophobic moiety, and at least 50% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in the variant is a hydrophobic moiety, and at least 55% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in the variant is a hydrophobic moiety, and at least 60% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in the variant is a hydrophobic moiety, and at least 65% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in the variant is a hydrophobic moiety, and at least 70% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in the variant is a hydrophobic moiety, and at least 75% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in the variant is a hydrophobic moiety and at least 80% of the amino acids of Y are selected from I, V, L, F, C, M and A. In some embodiments, Y in the variant is a hydrophobic moiety and at least 85% of the amino acids of Y are selected from I, V, L, F, C, M and A. In some embodiments, Y in the variant is a hydrophobic moiety and at least 90% of the amino acids of Y are selected from I, V, L, F, C, M and A.

[0202] In another aspect, variants of the artificial polypeptide of formula (IV) are provided.

[0203] In some embodiments, at least 20% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 25% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 30% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 35% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 40% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 45% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 50% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 55% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 60% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 65% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 70% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 75% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 80% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 85% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 90% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H.

[0204] In some embodiments, X in the variant comprises 40-65 amino acids, and the total number of hydrophilic amino acids in X is greater than 10. In some embodiments, X in the variant comprises 40-65 amino acids, and the total number of hydrophilic amino acids in X is greater than 15. In some embodiments, X in the variant comprises 40-65 amino acids, and the total number of hydrophilic amino acids in X is greater than 20. In some embodiments, X in the variant comprises 40-65 amino acids, and the total number of hydrophilic amino acids in X is greater than 25. In some embodiments, X in the variant comprises 40-65 amino acids, and the total number of hydrophilic amino acids in X is greater than 30. In some embodiments, X in the variant comprises 40-65 amino acids, and the total number of hydrophilic amino acids in X is greater than 35.

[0205] In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 15 or less. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 14 or less. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 13 or less. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 12 or less. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 11 or less. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 10 or less. In some embodiments, X in the variant is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 5 or less.

[0206] In some embodiments, X in the variant comprises a sequence having at least 70% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 75% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 80% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 85% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 90% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 95% identity to SEQ ID NO:1.

[0207] In some embodiments, Y in the variant is a moiety comprising a sequence having at least 70% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising a sequence having at least 75% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising a sequence having at least 80% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising a sequence having at least 85% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising a sequence having at least 90% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising a sequence having at least 95% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO:2. In some embodiments, Y in the variant is a moiety comprising the sequence of SEQ ID NO:2. In some embodiments, Y in the variant is a moiety which is the sequence of SEQ ID NO:2.

[0208] In some embodiments, Y in the variant is a hydrophobic moiety, and at least 50% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in the variant is a hydrophobic moiety, and at least 55% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in the variant is a hydrophobic moiety, and at least 60% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in the variant is a hydrophobic moiety, and at least 65% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in the variant is a hydrophobic moiety, and at least 70% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in the variant is a hydrophobic moiety, and at least 75% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in the variant is a hydrophobic moiety and at least 80% of the amino acids of Y are selected from I, V, L, F, C, M and A. In some embodiments, Y in the variant is a hydrophobic moiety and at least 85% of the amino acids of Y are selected from I, V, L, F, C, M and A. In some embodiments, Y in the variant is a hydrophobic moiety and at least 90% of the amino acids of Y are selected from I, V, L, F, C, M and A.

[0209] In another aspect, variants of the artificial polypeptide of formula (V) are provided.

[0210] In some embodiments, at least 20% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 25% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 30% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 35% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 40% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 45% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 50% of the amino acids of X in the variant are selected from R, K, N, D, Q, E, and H. In some embodiments, up to 55% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 60% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 65% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 70% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 75% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 80% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 85% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H. In some embodiments, up to 90% of the amino acids of X in the variant are selected from R, K, N, D, Q, E and H.

[0211] In some embodiments, Y in the variant comprises 10 to 25 amino acids. In some embodiments, Y in the variant comprises 10 to 20 amino acids. In some embodiments, Y in the variant comprises 10 to 15 amino acids. In some embodiments, Y in the variant comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids.

[0212] In some embodiments, X in the variant comprises a sequence having at least 70% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 75% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 80% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 85% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 90% identity to SEQ ID NO:1. In some embodiments, X in the variant comprises a sequence having at least 95% identity to SEQ ID NO:1.

[0213] In some embodiments, Y in the variant comprises a sequence that has at most 50% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 55% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 60% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 65% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 70% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 75% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 80% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 85% identity to SEQ ID NO:2. In some embodiments, Y in the variant comprises a sequence that has at most 90% identity to SEQ ID NO:2.

[0214] formulation In another aspect, provided herein is a formulation comprising an artificial polypeptide of the present disclosure, e.g., an artificial polypeptide of Formula (VI) or (VII), or a variant of the present disclosure, e.g., a variant of an artificial polypeptide of Formula (I), (II), (III), (IV), or (V), and a pharmaceutically acceptable excipient. For purposes of brevity, an artificial polypeptide of the present disclosure or a variant of the present disclosure may be referred to hereinafter as the "active ingredient."

[0215] The formulations described in this disclosure can be provided in any suitable form depending on the route of administration. In some embodiments, the formulations are formulated for oral, buccal, topical, transdermal, rectal, intranasal, intrapulmonary, transmucosal, inhalation, or parenteral administration, such as intravenous, intraarterial, intramuscular, subcutaneous, intraosseous, or intraperitoneal administration.

[0216] In some embodiments of the formulation, the formulation is in a form suitable for oral administration. In some embodiments, the formulation is in the form of a tablet, capsule, pill, powder, granule, liquid, suspension, or emulsion. The formulation may contain a predetermined amount of the active ingredient.

[0217] In some embodiments, the formulation is formulated as a tablet. The tablet may include a coating that protects the tablet from the acidic environment of the stomach. For example, the coating may be an enteric coating that maintains its integrity in the stomach and releases the active ingredient in the intestine. In some embodiments, the formulation is formulated as a capsule. The capsule may contain a liquid excipient such as a fatty oil. In some embodiments, the formulation is formulated as various liquid oral formulations, such as aqueous solutions, emulsions, or suspensions. In some embodiments, the liquid oral formulation is a solution and / or suspension reconstituted from non-effervescent or effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Elixirs are clear, sweetened hydroalcoholic preparations. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may contain one or more preservatives. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Emulsions may be oil-in-water or water-in-oil emulsions. The excipients used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions are heterogeneous mixtures in which solute particles do not dissolve but are suspended in the majority of the solvent, remaining freely floating in the medium. Suspensions use suspending agents and preservatives. Acceptable substances used in non-effervescent granules to be reconstituted into liquid oral formulations include diluents, sweeteners, and wetting agents. Acceptable substances used in effervescent granules to be reconstituted into liquid oral formulations include organic acids and carbon dioxide sources. Colorants and flavoring agents are used in all of the above formulations.

[0218] In some embodiments of the formulation, the formulation is in a form suitable for parenteral administration. In some embodiments, the formulation is in the form of a sterile injectable solution, suspension, emulsion, gel (e.g., injectable hydrogel), or sterile powder. The formulation may contain a predetermined amount of the active ingredient.

[0219] In some embodiments, the preparation is formulated as an injection. Examples of injections include, but are not limited to, sterile solutions, suspensions, or emulsions in aqueous or oily vehicles. For injections, aqueous solutions in saline are commonly used. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, cyclodextrin derivatives, and vegetable oils can also be used. Oily vehicles that can be used in injections include, but are not limited to, lipophilic solvents such as fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can also contain substances such as humectants, suspending agents, and / or flocculating or anti-flocculating agents. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. Preparations can also be formulated for bolus injection or continuous infusion. Alternatively, the formulation may be lyophilized or in powder form (ie, sterile powder for injection) for reconstitution with a suitable vehicle, such as sterile, pyrogen-free water, immediately before use.

[0220] In some embodiments of the formulation, the formulation is in a form suitable for topical administration. In some embodiments, the formulation is in the form of a spray, aerosol, inhalable powder, ointment, cream, patch, suppository, paste, film, or gel. The formulation may contain a predetermined amount of the active ingredient.

[0221] In some embodiments, the formulation is formulated as a topical formulation, such as for topical application to skin and mucous membranes. Useful topical formulations for active ingredients can be creams, gels, ointments, pastes, aerosols, sprays, suppositories, or any other formulation suitable for topical administration. For example, the active ingredient can also be formulated as an aerosol for topical application, such as by inhalation. These formulations for administration to the respiratory tract can be in the form of an aerosol for nebulizers, or can be fine powders for insufflation, alone or in combination with an inert carrier such as lactose. In such cases, the particles of the formulation have a mass median geometric diameter of less than 5 microns in some embodiments, and less than 10 microns in other embodiments.

[0222] In some embodiments of the formulation, the formulation is in the form of a sustained-release, controlled-release, or delayed-release formulation. In some embodiments, the formulation is in the form of a matrix tablet, a compressed tablet with mixed particles having different release rates, an osmotic pump tablet, an extended- or controlled-release capsule or microcapsule, an extended- or controlled-release implant, an extended- or controlled-release granule, a microparticle or microsphere, an enteric-coated capsule or tablet, a colon-located formulation, a gel (e.g., a hydrogel), a liposomal formulation, an ion-exchange resin formulation, a floating formulation, a bioadhesive formulation, a stimuli-inducing release formulation, and a pulsatile drug delivery system.

[0223] In some embodiments, the preparation is formulated as a sustained-release preparation.Examples of sustained-release preparations include, but are not limited to, shaped articles formed by semipermeable matrices of solid hydrophobic polymers (for example, sustained-release (micro)capsules).Examples of sustained-release matrices include, but are not limited to, hydrogels, polylactides, polyesters, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, and poly-D-(-)-3-hydroxybutyric acid.

[0224] In some embodiments, the formulation is formulated as a controlled-release formulation. Such formulations can be used to provide controlled release of one or more active ingredients, using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide desired release profiles at different rates. All controlled-release formulations share the common goal of improving drug therapy over that achieved by their non-controlled counterparts. Most controlled-release formulations are designed to initially release an amount of active ingredient that rapidly produces the desired preventive or therapeutic effect, and then gradually and continuously release other amounts of the active ingredient to maintain this level of preventive or therapeutic effect over an extended period of time. To maintain this constant level of active ingredient in the body, the active ingredient must be released from the formulation at a rate that replaces the amount of active ingredient metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions, including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions. Advantages of controlled-release formulations include extended activity of the active ingredient, reduced dosing frequency, and improved patient compliance. Moreover, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the active ingredient, and can thus affect the occurrence of unwanted side effects. An appropriate controlled-release formulation can be readily selected for use with the active ingredients provided in the present disclosure.

[0225] In some embodiments, the formulation is for use in humans.

[0226] In some embodiments, the formulation is a veterinary formulation.

[0227] In some embodiments, the formulation is formulated and administered in a unit-dosage form or multiple-dosage form. As used in this disclosure, unit-dosage form refers to a physically separate unit packaged individually, suitable for the subject in need thereof, as known in the art. Each unit-dosage contains a predetermined amount of active ingredient sufficient to produce the desired preventive or therapeutic effect, in combination with one or more pharmaceutically acceptable excipients. Examples of unit-dosage forms include, but are not limited to, ampoules and syringes, and individually packaged tablets or capsules. A unit-dosage form can be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single package to be administered in separate unit-dosage forms. Examples of multiple-dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple-dosage form is a plurality of unit doses that are not separated in packaging.

[0228] The formulations described in this disclosure can be prepared using procedures well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)). The procedures typically include combining the active ingredient with one or more pharmaceutically acceptable excipients. In general, formulations are prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired form. For example, tablets can be prepared by compressing or molding the active ingredient, optionally with one or more pharmaceutically acceptable auxiliary excipients. If the active ingredient exhibits insufficient solubility, solubilization methods such as the use of liposomes, prodrugs, complexation / chelation, nanoparticles, or emulsions or tertiary templating can be used.

[0229] Any pharmaceutically acceptable excipient routinely used in the pharmaceutical industry can be used to prepare the formulations described in this disclosure.Examples of pharmaceutically acceptable excipients useful in preparing the formulations described in this disclosure include solvents such as water, ethanol, glycerin, propylene glycol, DMSO, polyethylene glycol, fatty oils such as sesame oil, corn oil, cottonseed oil, or peanut oil, liquid paraffin, ethyl oleate, or isopropyl myristate; surfactants such as sulfates, sulfonates, quaternary ammonium compounds, lecithin, Span®, Tween®, Myri, polyoxyl 40 stearate, Peregol O, or Poloxamer; emulsifiers, such as gelatin, acacia, tragacanth, bentonite, or surfactants, such as polyoxyethylene sorbitan monooleate; suspending agents, such as sodium carboxymethylcellulose, pectin, tragacanth, Veegum, or acacia; fillers, such as lactose, sucrose, trehalose, lysine, leucine, kaolin, dicalcium phosphate, mannitol, microcrystalline cellulose, or pregelatinized starch; adhesives, such as cellulose, PVP, or dextrin; disintegrants, such as chrysanthemum, sorbitan monooleate, or sorbitan monooleate. roscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar or hydroxypropyl starch; lubricants such as talc, polyethylene glycol, calcium stearate, magnesium stearate, lycopodium or stearic acid; glidants such as colloidal silicon dioxide; coloring agents such as any of the approved certified water-soluble FD and C dyes or water-insoluble FD and C dyes (e.g., suspended in alumina hydrate); wetting agents such as propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate or polyoxyethylene lauryl ether; enteric coating agents such as fatty acids, fats, waxes, shellac, ammoniated shellac or cellulose acetate phthalate; film coating agents such as hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 or cellulose acetate phthalate; release-modifying agents such as Eudragit. 登録商標series and polymers such as cellulose esters; sweeteners, for example, fructose, glucose, sucrose, sucralose, artificial sweeteners such as aspartame or saccharin, agave syrup, maple syrup or corn syrup; flavoring agents, for example, natural flavors extracted from plants such as fruits, peppermint or methyl salicylate; buffers, for example, citrate, phosphate, and other organic acids and / or their salts; antioxidants, for example, ascorbic acid, methionine, citric acid, D,L-α-tocopherol, These may include, but are not limited to, BHA, BHT, monothioglycerol, ascorbyl palmitate, ascorbic acid, or propyl gallate; preservatives, such as benzoic acid, sodium benzoate, parabens such as methylparaben or propylparaben, sorbic acid, or benzalkonium bromide; pH adjusters, such as citric acid, sodium citrate, hydrochloric acid, NaOH, or other weak acids or bases; and chelating agents or other materials capable of binding metal ions, such as ethylenediaminetetraacetic acid (EDTA) or its salts.

[0230] The level of active ingredient in the formulations described herein is effective for delivery of an amount that, upon administration, treats, results in prevention of, or results in the alleviation of one or more symptoms of a disease or condition described herein. Specifically, the amount of active ingredient described herein will depend on the subject being treated, the severity of the disease or condition, the rate of administration, the absorption, inactivation, and excretion rate of the administered active ingredient, the discretion of the prescribing physician, and other factors known to those skilled in the art. In some embodiments, the formulation contains 0.05%-80%, 0.1%-50%, 0.2%-40%, 0.5%-25%, 1%-20%, 5%-15%, or 7%-12% (w / w) of an active ingredient described herein. The remainder of the formulation consists of one or more pharmaceutically acceptable excipients.

[0231] Alternatively, in some embodiments, the formulation comprises from about 0.001 μM to about 100 μM of the active ingredient. In some embodiments, the formulation comprises from about 0.01 μM to about 20 μM of the active ingredient. In some embodiments, the formulation comprises from about 0.1 μM to about 5 μM of the active ingredient. In some embodiments, the formulation comprises from about 0.2 μM to about 3 μM of the active ingredient. In some embodiments, the formulation comprises from about 0.1 μM to about 10 μM of the active ingredient. In some embodiments, the formulation comprises from about 1 μM to about 5 μM of the active ingredient. In some embodiments, the formulation comprises from about 1 μM to about 10 μM of the active ingredient. In some embodiments, the formulation comprises from about 5 μM to about 10 μM of the active ingredient. In some embodiments, the formulation comprises from about 10 μM to about 50 μM of the active ingredient. In some embodiments, the formulation comprises from about 20 μM to about 50 μM of the active ingredient. In some embodiments, the formulation comprises about 5 μM to about 50 μM of the active ingredient. In some embodiments, the formulation comprises about 1 μM to about 50 μM of the active ingredient. In some embodiments, the formulation comprises about 1 μM to about 20 μM of the active ingredient. In some embodiments, the formulation comprises about 5 μM to about 20 μM of the active ingredient. In some embodiments, the formulation comprises about 10 μM to about 20 μM of the active ingredient. In some embodiments, the formulation contains greater than about 0.001, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2, 8, 2.9, or 3.0 μM of the active ingredient. In some embodiments, the formulation contains less than 100, 90, 80, 70, 60, 50, 40, 30, 20, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, or 4 μM of the active ingredient. Methods of Treatment and Therapeutic Uses

[0232] In one aspect, there is provided a method for treating or preventing pain in a subject in need thereof, comprising: an effective amount of an artificial polypeptide of formula (I): XY(I), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1, and Y is a moiety comprising 10 to 50 amino acids, at least 50% of which are selected from I, V, L, F, C, M and A; Y contains a total number of cysteines (C) of less than 5 to said subject.

[0233] In some embodiments, X in Formula (I) can be a hydrophilic moiety, at least 50% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in Formula (I) can be a hydrophilic moiety, at least 55% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in Formula (I) can be a hydrophilic moiety, at least 60% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in Formula (I) can be a hydrophilic moiety, at least 65% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in Formula (I) can be a hydrophilic moiety, at least 70% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in Formula (I) can be a hydrophilic moiety, at least 75% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (I) can be a hydrophilic moiety, at least 80% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (I) can be a hydrophilic moiety, at least 85% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (I) can be a hydrophilic moiety, at least 90% of which are selected from R, K, N, D, Q, E, and H.

[0234] In some embodiments, X in formula (I) can be a moiety comprising a sequence having at least 80% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising a sequence having at least 85% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising a sequence having at least 90% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising a sequence having at least 95% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising the sequence of SEQ ID NO:1. In some embodiments, X is a moiety that is the sequence of SEQ ID NO:1.

[0235] In some embodiments, Y in formula (I) can be a hydrophobic moiety, at least 50% of which are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (I) can be a hydrophobic moiety, at least 55% of which are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (I) can be a hydrophobic moiety, at least 60% of which are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (I) can be a hydrophobic moiety, at least 65% of which are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (I) can be a hydrophobic moiety, at least 70% of which are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (I) can be a hydrophobic moiety, at least 75% of which are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (I) can be a hydrophobic moiety, at least 80% of which are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (I) can be a hydrophobic moiety, at least 85% of which are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (I) can be a hydrophobic moiety, at least 90% of which are selected from I, V, L, F, C, M, and A.

[0236] In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of hydrophobic amino acids in Y is 5. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of hydrophobic amino acids in Y is greater than 5. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of hydrophobic amino acids in Y is 6. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of hydrophobic amino acids in Y is greater than 6. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of hydrophobic amino acids in Y is 7. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of hydrophobic amino acids in Y is greater than 7. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of hydrophobic amino acids in Y is 8. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is greater than 8. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is 9. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is greater than 9. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is 10. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is greater than 10. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is 11. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is greater than 11. In some embodiments, Y in formula (I) can be a moiety comprising 10-50 amino acids, and the total number of hydrophobic amino acids in Y is 12. In some embodiments, Y in formula (I) can be a moiety comprising 10-50 amino acids, and the total number of hydrophobic amino acids in Y is greater than 12.In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is 13. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is greater than 13. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is 14. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is greater than 14. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is 15. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of hydrophobic amino acids in Y is greater than 15.

[0237] In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of I, V, L, F, C, M, and A in Y is 5. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of I, V, L, F, C, M, and A in Y is greater than 5. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of I, V, L, F, C, M, and A in Y is 6. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of I, V, L, F, C, M, and A in Y is greater than 6. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of I, V, L, F, C, M, and A in Y is 7. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, wherein the total number of I, V, L, F, C, M, and A in Y is greater than 7. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, wherein the total number of I, V, L, F, C, M, and A in Y is greater than 8. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, wherein the total number of I, V, L, F, C, M, and A in Y is greater than 8. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, wherein the total number of I, V, L, F, C, M, and A in Y is 9. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, wherein the total number of I, V, L, F, C, M, and A in Y is greater than 9. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of I, V, L, F, C, M, and A in Y is 10. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of I, V, L, F, C, M, and A in Y is greater than 10. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of I, V, L, F, C, M, and A in Y is 11. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, wherein the total number of I, V, L, F, C, M, and A in Y is greater than 11.In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of I, V, L, F, C, M, and A in Y is 12. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of I, V, L, F, C, M, and A in Y is greater than 12. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of I, V, L, F, C, M, and A in Y is 13. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of I, V, L, F, C, M, and A in Y is greater than 13. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of I, V, L, F, C, M, and A in Y is 14. In some embodiments, Y in formula (I) can be a moiety comprising 10-50 amino acids, wherein the total number of I, V, L, F, C, M, and A in Y is greater than 14. In some embodiments, Y in formula (I) can be a moiety comprising 10-50 amino acids, wherein the total number of I, V, L, F, C, M, and A in Y is 15. In some embodiments, Y in formula (I) can be a moiety comprising 10-50 amino acids, wherein the total number of I, V, L, F, C, M, and A in Y is greater than 15.

[0238] In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of cysteines (C) in Y is 5. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of cysteines (C) in Y is less than 5. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of cysteines (C) in Y is 4. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of cysteines (C) in Y is less than 4. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of cysteines (C) in Y is 3. In some embodiments, Y in formula (I) can be a moiety containing 10 to 50 amino acids, and the total number of cysteines (C) in Y is less than 3. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, and the total number of cysteines (C) in Y is 2. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, and the total number of cysteines (C) in Y is less than 2. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, and the total number of cysteines (C) in Y is 1. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, and the total number of cysteines (C) in Y is less than 1. In some embodiments, Y in formula (I) can be a moiety comprising 10 to 50 amino acids, and the total number of cysteines (C) in Y is 0.

[0239] In some embodiments, the total number of hydrophilic amino acids in Y, of formula (I) is 5. In some embodiments, the total number of hydrophilic amino acids in Y, of formula (I) is 5 or less. In some embodiments, the total number of hydrophilic amino acids in Y, of formula (I) is 4. In some embodiments, the total number of hydrophilic amino acids in Y, of formula (I) is 4 or less. In some embodiments, the total number of hydrophilic amino acids in Y, of formula (I) is 3. In some embodiments, the total number of hydrophilic amino acids in Y, of formula (I) is 3 or less. In some embodiments, the total number of hydrophilic amino acids in Y, of formula (I) is 2. In some embodiments, the total number of hydrophilic amino acids in Y, of formula (I) is 2 or less. In some embodiments, the total number of hydrophilic amino acids in Y, of formula (I) is 1. In some embodiments, the total number of hydrophilic amino acids in Y, of formula (I) is 1 or less.

[0240] In some embodiments, the total number of R, K, N, D, Q, E, and H in Y of formula (I) is 5. In some embodiments, the total number of R, K, N, D, Q, E, and H in Y of formula (I) is 5 or less. In some embodiments, the total number of hydrophilic amino acids in Y of formula (I) is 4. In some embodiments, the total number of R, K, N, D, Q, E, and H in Y of formula (I) is 4 or less. In some embodiments, the total number of R, K, N, D, Q, E, and H in Y of formula (I) is 3. In some embodiments, the total number of R, K, N, D, Q, E, and H in Y of formula (I) is 3 or less. In some embodiments, the total number of R, K, N, D, Q, E, and H in Y of formula (I) is 2. In some embodiments, the total number of R, K, N, D, Q, E, and H in Y of formula (I) is 2 or less. In some embodiments, the total number of R, K, N, D, Q, E, and H in Y of formula (I) is 1. In some embodiments, the total number of R, K, N, D, Q, E, and H in Y of formula (I) is 1 or less.

[0241] In some embodiments of the artificial polypeptide, X in Formula (I) comprises a sequence at least 70% identical to any one of SEQ ID NOs: 81-83. In some embodiments of the artificial polypeptide, X in Formula (I) comprises a sequence at least 75% identical to any one of SEQ ID NOs: 81-83. In some embodiments of the artificial polypeptide, X in Formula (I) comprises a sequence at least 80% identical to any one of SEQ ID NOs: 81-83. In some embodiments of the artificial polypeptide, X in Formula (I) comprises a sequence at least 85% identical to any one of SEQ ID NOs: 81-83. In some embodiments of the artificial polypeptide, X in Formula (I) comprises a sequence at least 90% identical to any one of SEQ ID NOs: 81-83. In some embodiments of the artificial polypeptide, X in Formula (I) comprises a sequence at least 95% identical to any one of SEQ ID NOs: 81-83. In some embodiments of the artificial polypeptide, X of Formula (I) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 81-83. In some embodiments of the artificial polypeptide, X of Formula (I) comprises any one sequence selected from SEQ ID NOs: 81-83. In some embodiments of the artificial polypeptide, X of Formula (I) is any one sequence selected from SEQ ID NOs: 81-83.

[0242] In some embodiments of the artificial polypeptide, Y of Formula (I) comprises a sequence having at least 70% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments of the artificial polypeptide, Y of Formula (I) comprises a sequence having at least 75% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments of the artificial polypeptide, Y of Formula (I) comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments of the artificial polypeptide, Y of Formula (I) comprises a sequence having at least 85% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments of the artificial polypeptide, Y of Formula (I) comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments of the artificial polypeptide, Y of Formula (I) comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments of the artificial polypeptide, Y of Formula (I) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments of the artificial polypeptide, Y of Formula (I) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 3-15, 58-61, and 84-85. In some embodiments of the artificial polypeptide, Y of formula (I) is any one sequence selected from SEQ ID NOs: 3-15, 58-61, and 84-85.

[0243] In some embodiments of an artificial polypeptide of Formula (I), the polypeptide comprises a sequence having at least 70% identity to any one selected from SEQ ID NOs: 29-41, 54-57, 75, and 91-95. In some embodiments of an artificial polypeptide of Formula (I), the polypeptide comprises a sequence having at least 75% identity to any one selected from SEQ ID NOs: 29-41, 54-57, 75, and 91-95. In some embodiments of an artificial polypeptide of Formula (I), the polypeptide comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 29-41, 54-57, 75, and 91-95. In some embodiments of an artificial polypeptide of Formula (I), the polypeptide comprises a sequence having at least 85% identity to any one selected from SEQ ID NOs: 29-41, 54-57, 75, and 91-95. In some embodiments of an artificial polypeptide of Formula (I), the polypeptide comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 29-41, 54-57, 75, and 91-95. In some embodiments of an artificial polypeptide of Formula (I), the polypeptide comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 29-41, 54-57, 75, and 91-95. In some embodiments of an artificial polypeptide of Formula (I), the polypeptide comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 29-41, 54-57, 75, and 91-95. In some embodiments of an artificial polypeptide of Formula (I), the polypeptide comprises a sequence having at least one of SEQ ID NOs: 29-41, 54-57, 75, and 91-95. In some embodiments of the artificial polypeptide of Formula (I), the polypeptide is the sequence of any one of SEQ ID NOs: 29-41, 54-57, 75, and 91-95.

[0244] In another aspect, there is provided a method for treating or preventing pain in a subject in need thereof, comprising: an effective amount of an artificial polypeptide of formula (II): XY(II), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1, and Y is a moiety comprising 10 to 50 amino acids, at least 50% of which are selected from I, V, L, F, C, M and A; Y comprises a sequence having at most 90% identity to SEQ ID NO: 2 to said subject.

[0245] In some embodiments, X in formula (II) can be a hydrophilic moiety, at least 50% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (II) can be a hydrophilic moiety, at least 55% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (I) can be a hydrophilic moiety, at least 60% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (II) can be a hydrophilic moiety, at least 65% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (II) can be a hydrophilic moiety, at least 70% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in (II) can be a hydrophilic moiety, at least 75% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (II) can be a hydrophilic moiety, at least 80% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (II) can be a hydrophilic moiety, at least 85% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (II) can be a hydrophilic moiety, at least 90% of which are selected from R, K, N, D, Q, E, and H.

[0246] In some embodiments, X in Formula (II) can be a hydrophilic moiety comprising one or more arginines (R). For example, X in Formula (II) can be a hydrophilic moiety comprising at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 arginines (R). In some embodiments, X in Formula (II) can be a hydrophilic moiety comprising one or more lysines (K). For example, X in Formula (II) can be a hydrophilic moiety comprising at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 lysines (K). In some embodiments, X in Formula (II) can be a hydrophilic moiety comprising one or more asparagines (N). For example, X in Formula (II) can be a hydrophilic moiety comprising at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 asparagines (N). In some embodiments, X in Formula (II) can be a hydrophilic moiety comprising one or more aspartic acids (D). For example, X in Formula (II) can be a hydrophilic moiety comprising at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 aspartic acids (D). In some embodiments, X in Formula (II) can be a hydrophilic moiety comprising one or more glutamines (Q). For example, X in Formula (II) can be a hydrophilic moiety comprising at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 glutamines (Q). In some embodiments, X in Formula (II) can be a hydrophilic moiety comprising one or more glutamic acids (E). For example, X in Formula (II) can be a hydrophilic moiety comprising at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 glutamic acids (E).In some embodiments, X of Formula (II) can be a hydrophilic moiety that includes one or more histidines (H). For example, X of Formula (II) can be a hydrophilic moiety that includes at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 histidines (H).

[0247] In some embodiments, X in formula (II) can be a moiety comprising a sequence having at least 80% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising a sequence having at least 85% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising a sequence having at least 90% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising a sequence having at least 95% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising the sequence of SEQ ID NO:1. In some embodiments, X is a moiety that is the sequence of SEQ ID NO:1.

[0248] In some embodiments of the artificial polypeptide of Formula (II), Y comprises a sequence having at most 50% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 55% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 60% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 65% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 70% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 75% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 80% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 85% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 90% identity to SEQ ID NO:2.

[0249] In some embodiments of an artificial polypeptide of Formula (II), Y comprises a sequence at least 70% identical to any one of SEQ ID NOs: 16-18. In some embodiments of an artificial polypeptide, Y comprises a sequence at least 75% identical to any one of SEQ ID NOs: 16-18. In some embodiments of an artificial polypeptide, Y comprises a sequence at least 80% identical to any one of SEQ ID NOs: 16-18. In some embodiments of an artificial polypeptide, Y comprises a sequence at least 85% identical to any one of SEQ ID NOs: 16-18. In some embodiments of an artificial polypeptide, Y comprises a sequence at least 90% identical to any one of SEQ ID NOs: 16-18. In some embodiments of an artificial polypeptide, Y comprises a sequence at least 95% identical to any one of SEQ ID NOs: 16-18. In some embodiments of the artificial polypeptide, Y comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 16-18. In some embodiments of the artificial polypeptide, Y comprises any one sequence selected from SEQ ID NOs: 16-18. In some embodiments of the artificial polypeptide, Y is any one sequence selected from SEQ ID NOs: 16-18.

[0250] In some embodiments of an artificial polypeptide of Formula (II), the artificial polypeptide comprises a sequence at least 70% identical to any one of SEQ ID NOs: 42-44. In some embodiments of an artificial polypeptide, the artificial polypeptide comprises a sequence at least 75% identical to any one of SEQ ID NOs: 42-44. In some embodiments of an artificial polypeptide, the artificial polypeptide comprises a sequence at least 80% identical to any one of SEQ ID NOs: 42-44. In some embodiments of an artificial polypeptide, the artificial polypeptide comprises a sequence at least 85% identical to any one of SEQ ID NOs: 42-44. In some embodiments of an artificial polypeptide, the artificial polypeptide comprises a sequence at least 90% identical to any one of SEQ ID NOs: 42-44. In some embodiments of an artificial polypeptide, the artificial polypeptide comprises a sequence at least 95% identical to any one of SEQ ID NOs: 42-44. In some embodiments of the artificial polypeptide, the artificial polypeptide comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 42-44. In some embodiments of the artificial polypeptide, the artificial polypeptide comprises any one sequence selected from SEQ ID NOs: 42-44. In some embodiments of the artificial polypeptide, the artificial polypeptide is any one sequence selected from SEQ ID NOs: 42-44.

[0251] In another aspect, there is provided a method for treating or preventing pain in a subject in need thereof, comprising: an effective amount of an artificial polypeptide of formula (III): XY(III), wherein X is a moiety comprising 40 to 65 amino acids, at least 50% of which are selected from H, R, K, D, Q, N, and E; and Y is a moiety containing a sequence having at least 80% identity with SEQ ID NO: 2, and the total number of H, R, K, D, Q, N, and E in X is less than 33. to said subject.

[0252] In some embodiments, X in Formula (III) can be a hydrophilic moiety, at least 50% of which are selected from H, R, K, D, Q, N, and E. In some embodiments, X in Formula (III) can be a hydrophilic moiety, at least 55% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in Formula (III) can be a hydrophilic moiety, at least 60% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in Formula (III) can be a hydrophilic moiety, at least 65% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in Formula (III) can be a hydrophilic moiety, at least 70% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in Formula (III) can be a hydrophilic moiety, at least 75% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (III) can be a hydrophilic moiety, at least 80% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (III) can be a hydrophilic moiety, at least 85% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (III) can be a hydrophilic moiety, at least 90% of which are selected from R, K, N, D, Q, E, and H.

[0253] In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 33. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 32. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 31. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 30. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 29. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 28. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 27. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 26. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 25. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 24. In some embodiments, X in formula (III) is a moiety comprising 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 23. In some embodiments, X in formula (III) is a moiety comprising 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 22. In some embodiments, X in formula (III) is a moiety comprising 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 21. In some embodiments, X in formula (III) is a moiety comprising 40 to 65 amino acids, and the total number of H, R, K, D, Q, N, and E in X is less than 20.

[0254] In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 10. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 11. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 12. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 13. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 14. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 15. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 16. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 17. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 18. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 19. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 20. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 21. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 22. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 23. In some embodiments, X of formula (III) is a moiety comprising 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 24. In some embodiments, X of formula (III) is a moiety comprising 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 25.

[0255] In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 15 or less. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 14 or less. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 13 or less. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 12 or less. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 11 or less. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 10 or less. In some embodiments, X in formula (III) is a moiety containing 40 to 65 amino acids, and the total number of hydrophobic amino acids in X is 5 or less.

[0256] In some embodiments, X in formula (III) comprises a sequence having at least 70% identity to any one selected from SEQ ID NOs: 23-27. In some embodiments, X in formula (III) comprises a sequence having at least 75% identity to any one selected from SEQ ID NOs: 23-27. In some embodiments, X in formula (III) comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 23-27. In some embodiments, X in formula (III) comprises a sequence having at least 85% identity to any one selected from SEQ ID NOs: 23-27. In some embodiments, X in formula (III) comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 23-27. In some embodiments, X in formula (III) comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 23-27. In some embodiments, X of formula (III) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 23 to 27. In some embodiments, X of formula (III) comprises any one sequence selected from SEQ ID NOs: 23 to 27. In some embodiments, X of formula (III) is any one sequence selected from SEQ ID NOs: 23 to 27.

[0257] In some embodiments, Y in formula (III) is a moiety comprising a sequence having at least 70% identity to SEQ ID NO:2. In some embodiments, Y in formula (III) is a moiety comprising a sequence having at least 75% identity to SEQ ID NO:2. In some embodiments, Y in formula (III) is a moiety comprising a sequence having at least 80% identity to SEQ ID NO:2. In some embodiments, Y in formula (III) is a moiety comprising a sequence having at least 85% identity to SEQ ID NO:2. In some embodiments, Y in formula (III) is a moiety comprising a sequence having at least 90% identity to SEQ ID NO:2. In some embodiments, Y in formula (III) is a moiety comprising a sequence having at least 95% identity to SEQ ID NO:2. In some embodiments, Y in formula (III) is a moiety comprising a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO:2. In some embodiments, Y in formula (III) is a moiety comprising the sequence of SEQ ID NO:2. In some embodiments, Y in formula (III) is a moiety that is the sequence of SEQ ID NO:2.

[0258] In some embodiments, Y in formula (III) is a hydrophobic moiety, and at least 50% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (III) is a hydrophobic moiety, and at least 55% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (III) is a hydrophobic moiety, and at least 60% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (III) is a hydrophobic moiety, and at least 65% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (III) is a hydrophobic moiety, and at least 70% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (III) is a hydrophobic moiety, and at least 75% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y of formula (III) is a hydrophobic moiety, and at least 80% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y of formula (III) is a hydrophobic moiety, and at least 85% of the amino acids of Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y of formula (III) is a hydrophobic moiety, and at least 90% of the amino acids of Y are selected from I, V, L, F, C, M, and A.

[0259] In some embodiments, an artificial polypeptide of Formula (III) comprises a sequence at least 70% identical to any one of SEQ ID NOs: 49-53. In some embodiments, an artificial polypeptide of Formula (III) comprises a sequence at least 75% identical to any one of SEQ ID NOs: 49-53. In some embodiments, an artificial polypeptide of Formula (III) comprises a sequence at least 80% identical to any one of SEQ ID NOs: 49-53. In some embodiments, an artificial polypeptide of Formula (III) comprises a sequence at least 85% identical to any one of SEQ ID NOs: 49-53. In some embodiments, an artificial polypeptide of Formula (III) comprises a sequence at least 90% identical to any one of SEQ ID NOs: 49-53. In some embodiments, an artificial polypeptide of Formula (III) comprises a sequence at least 95% identical to any one of SEQ ID NOs: 49-53. In some embodiments, the artificial polypeptide of Formula (III) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 49-53. In some embodiments, the artificial polypeptide of Formula (III) comprises any one sequence selected from SEQ ID NOs: 49-53. In some embodiments, the artificial polypeptide of Formula (III) is any one sequence selected from SEQ ID NOs: 49-53.

[0260] In another aspect, there is provided a method for treating or preventing pain in a subject in need thereof, comprising: an effective amount of an artificial polypeptide of formula (IV): XY(IV), wherein X is a moiety comprising 40 to 65 amino acids, at least 50% of which are selected from H, R, K, D, Q, N, and E; and Y is a moiety comprising a sequence having at least 80% identity with SEQ ID NO:2, and X comprises a sequence having at most 90% identity with SEQ ID NO:1. to said subject.

[0261] In some embodiments, X in formula (IV) can be a hydrophilic moiety, at least 50% of which are selected from H, R, K, D, Q, N, and E. In some embodiments, X in formula (IV) can be a hydrophilic moiety, at least 55% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (IV) can be a hydrophilic moiety, at least 60% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (IV) can be a hydrophilic moiety, at least 65% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (IV) can be a hydrophilic moiety, at least 70% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (IV) can be a hydrophilic moiety, at least 75% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (IV) can be a hydrophilic moiety, at least 80% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (IV) can be a hydrophilic moiety, at least 85% of which are selected from R, K, N, D, Q, E, and H. In some embodiments, X in formula (IV) can be a hydrophilic moiety, at least 90% of which are selected from R, K, N, D, Q, E, and H.

[0262] In some embodiments, X in formula (IV) comprises 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 10. In some embodiments, X in formula (IV) comprises 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 15. In some embodiments, X in formula (IV) comprises 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 20. In some embodiments, X in formula (IV) comprises 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 25. In some embodiments, X in formula (IV) comprises 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 30. In some embodiments, X in formula (IV) comprises 40 to 65 amino acids, and the total number of hydrophilic amino acids in X is greater than 35.

[0263] In some embodiments, X of formula (IV) comprises a sequence having at most 50% identity to SEQ ID NO:1. In some embodiments, X of formula (IV) comprises a sequence having at most 55% identity to SEQ ID NO:1. In some embodiments, X of formula (IV) comprises a sequence having at most 60% identity to SEQ ID NO:1. In some embodiments, X of formula (IV) comprises a sequence having at most 65% identity to SEQ ID NO:1. In some embodiments, X of formula (IV) comprises a sequence having at most 70% identity to SEQ ID NO:1. In some embodiments, X of formula (IV) comprises a sequence having at most 75% identity to SEQ ID NO:1. In some embodiments, X of formula (IV) comprises a sequence having at most 80% identity to SEQ ID NO:1. In some embodiments, X of formula (IV) comprises a sequence having at most 85% identity to SEQ ID NO:1. In some embodiments, X of formula (IV) comprises a sequence having at most 90% identity to SEQ ID NO:1.

[0264] In some embodiments, Y in formula (IV) is a moiety comprising a sequence having at least 70% identity to SEQ ID NO:2. In some embodiments, Y in formula (IV) is a moiety comprising a sequence having at least 75% identity to SEQ ID NO:2. In some embodiments, Y in formula (IV) is a moiety comprising a sequence having at least 80% identity to SEQ ID NO:2. In some embodiments, Y in formula (IV) is a moiety comprising a sequence having at least 85% identity to SEQ ID NO:2. In some embodiments, Y in formula (IV) is a moiety comprising a sequence having at least 90% identity to SEQ ID NO:2. In some embodiments, Y in formula (IV) is a moiety comprising a sequence having at least 95% identity to SEQ ID NO:2. In some embodiments, Y in formula (IV) is a moiety comprising a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO:2. In some embodiments, Y in formula (IV) is a moiety comprising the sequence of SEQ ID NO:2. In some embodiments, Y in formula (IV) is a moiety that is the sequence of SEQ ID NO:2.

[0265] In some embodiments, Y in formula (IV) is a hydrophobic moiety, and at least 50% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (IV) is a hydrophobic moiety, and at least 55% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (IV) is a hydrophobic moiety, and at least 60% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (IV) is a hydrophobic moiety, and at least 65% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (IV) is a hydrophobic moiety, and at least 70% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (IV) is a hydrophobic moiety, and at least 75% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (IV) is a hydrophobic moiety, and at least 80% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (IV) is a hydrophobic moiety, and at least 85% of the amino acids in Y are selected from I, V, L, F, C, M, and A. In some embodiments, Y in formula (IV) is a hydrophobic moiety, and at least 90% of the amino acids in Y are selected from I, V, L, F, C, M, and A.

[0266] In some embodiments, X in formula (IV) comprises a sequence having at least 70% identity to any one selected from SEQ ID NOs: 19-22 and 76-79. In some embodiments, X in formula (IV) comprises a sequence having at least 75% identity to any one selected from SEQ ID NOs: 19-22 and 76-79. In some embodiments, X in formula (IV) comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 19-22 and 76-79. In some embodiments, X in formula (IV) comprises a sequence having at least 85% identity to any one selected from SEQ ID NOs: 19-22 and 76-79. In some embodiments, X in formula (IV) comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 19-22 and 76-79. In some embodiments, X in formula (IV) comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 19-22 and 76-79. In some embodiments, X in formula (IV) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 19-22 and 76-79. In some embodiments, X in formula (IV) comprises any one sequence selected from SEQ ID NOs: 19-22 and 76-79. In some embodiments, X in formula (IV) is any one sequence selected from SEQ ID NOs: 19-22 and 76-79.

[0267] In some embodiments, an artificial polypeptide of Formula (IV) comprises a sequence at least 70% identical to any one selected from SEQ ID NOs: 45-48 and 86-89. In some embodiments, an artificial polypeptide of Formula (IV) comprises a sequence at least 75% identical to any one selected from SEQ ID NOs: 45-48 and 86-89. In some embodiments, an artificial polypeptide of Formula (IV) comprises a sequence at least 80% identical to any one selected from SEQ ID NOs: 45-48 and 86-89. In some embodiments, an artificial polypeptide of Formula (IV) comprises a sequence at least 85% identical to any one selected from SEQ ID NOs: 45-48 and 86-89. In some embodiments, an artificial polypeptide of Formula (IV) comprises a sequence at least 90% identical to any one selected from SEQ ID NOs: 45-48 and 86-89. In some embodiments, an artificial polypeptide of Formula (IV) comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 45-48 and 86-89. In some embodiments, an artificial polypeptide of Formula (IV) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 45-48 and 86-89. In some embodiments, an artificial polypeptide of Formula (IV) comprises a sequence selected from SEQ ID NOs: 45-48 and 86-89. In some embodiments, an artificial polypeptide of Formula (IV) is a sequence selected from SEQ ID NOs: 45-48 and 86-89.

[0268] In another aspect, there is provided a method for treating or preventing pain in a subject in need thereof, comprising: an effective amount of an artificial polypeptide of formula (V): XY(V), (wherein X is a moiety containing a sequence having at least 80% identity with SEQ ID NO: 1, and Y is a moiety containing 10 to 30 amino acids, and Y contains a sequence having at least 10 consecutive AA of SEQ ID NO: 2) to said subject.

[0269] In some embodiments, Y of formula (V) comprises 10 to 25 amino acids. In some embodiments, Y comprises 10 to 20 amino acids. In some embodiments, Y comprises 10 to 15 amino acids. In some embodiments, Y comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids.

[0270] In some embodiments, X in formula (V) can be a moiety comprising a sequence having at least 80% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising a sequence having at least 85% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising a sequence having at least 90% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising a sequence having at least 95% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO:1. In some embodiments, X is a moiety comprising the sequence of SEQ ID NO:1. In some embodiments, X is a moiety that is the sequence of SEQ ID NO:1.

[0271] In some embodiments of an artificial polypeptide of Formula (V), at least 50% of the amino acids in X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 55% of the amino acids in X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 60% of the amino acids in X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 65% of the amino acids in X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 70% of the amino acids in X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 75% of the amino acids in X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 80% of the amino acids in X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 85% of the amino acids in X are selected from R, K, N, D, Q, E, and H. In some embodiments, at least 90% of the amino acids in X are selected from R, K, N, D, Q, E, and H.

[0272] In some embodiments of an artificial polypeptide of Formula (V), X comprises a sequence having at least 70% identity to SEQ ID NO:96. In some embodiments of an artificial polypeptide of Formula (V), X comprises a sequence having at least 75% identity to SEQ ID NO:96. In some embodiments of an artificial polypeptide of Formula (V), X comprises a sequence having at least 80% identity to SEQ ID NO:96. In some embodiments, X comprises a sequence having at least 85% identity to SEQ ID NO:96. In some embodiments, X comprises a sequence having at least 90% identity to SEQ ID NO:96. In some embodiments, X comprises a sequence having at least 95% identity to SEQ ID NO:96. In some embodiments, X comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO:96. In some embodiments, X comprises the sequence of SEQ ID NO:96. In some embodiments, X is the sequence of SEQ ID NO:96.

[0273] In some embodiments of an artificial polypeptide of Formula (V), Y comprises a sequence having at most 50% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 55% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 60% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 65% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 70% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 75% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 80% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 85% identity to SEQ ID NO:2. In some embodiments, Y comprises a sequence having at most 90% identity to SEQ ID NO:2.

[0274] In some embodiments of an artificial polypeptide of Formula (V), Y comprises a sequence at least 70% identical to any one of SEQ ID NOs: 97-103. In some embodiments of an artificial polypeptide of Formula (V), Y comprises a sequence at least 75% identical to any one of SEQ ID NOs: 97-103. In some embodiments of an artificial polypeptide of Formula (V), Y comprises a sequence at least 80% identical to any one of SEQ ID NOs: 97-103. In some embodiments, Y comprises a sequence at least 85% identical to any one of SEQ ID NOs: 97-103. In some embodiments, Y comprises a sequence at least 90% identical to any one of SEQ ID NOs: 97-103. In some embodiments, Y comprises a sequence at least 95% identical to any one of SEQ ID NOs: 97-103. In some embodiments, Y comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 97-103. In some embodiments, Y comprises a sequence that is any one selected from SEQ ID NOs: 97-103. In some embodiments, Y is a sequence that is any one selected from SEQ ID NOs: 97-103.

[0275] In some embodiments, an artificial polypeptide of Formula (V) comprises a sequence at least 70% identical to any one selected from SEQ ID NOs: 53-56 and 104-110. In some embodiments, an artificial polypeptide of Formula (V) comprises a sequence at least 75% identical to any one selected from SEQ ID NOs: 53-56 and 104-110. In some embodiments, an artificial polypeptide of Formula (V) comprises a sequence at least 80% identical to any one selected from SEQ ID NOs: 53-56 and 104-110. In some embodiments, an artificial polypeptide of Formula (V) comprises a sequence at least 85% identical to any one selected from SEQ ID NOs: 53-56 and 104-110. In some embodiments, an artificial polypeptide of Formula (V) comprises a sequence at least 90% identical to any one selected from SEQ ID NOs: 53-56 and 104-110. In some embodiments, an artificial polypeptide of Formula (V) comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 53-56 and 104-110. In some embodiments, an artificial polypeptide of Formula (V) comprises a sequence having at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NOs: 53-56 and 104-110. In some embodiments, an artificial polypeptide of Formula (V) comprises a sequence selected from SEQ ID NOs: 53-56 and 104-110. In some embodiments, an artificial polypeptide of Formula (V) is any one sequence selected from SEQ ID NOs: 53-56 and 104-110.

[0276] In another aspect, there is provided a method for treating or preventing pain in a subject in need thereof, comprising administering to the subject an effective amount of an artificial polypeptide of Formula (VI) or (VII), or a variant of an artificial polypeptide of Formula (I), (II), (III), (IV), or (V). Exemplary embodiments of an artificial polypeptide of Formula (VI) or (VII), or a variant of an artificial polypeptide of Formula (I), (II), (III), (IV), or (V), are described above in the section entitled "Analgesic Polypeptides."

[0277] In another aspect, there is provided a method for treating or preventing peripheral neuropathic pain in a subject in need thereof, the method comprising administering to the subject an effective amount of a polypeptide having at least 70% identity to any one selected from SEQ ID NO: 28, SEQ ID NO: 57, and 62-74, or a fragment or variant thereof.

[0278] In some embodiments, the polypeptide has at least 70% identity to any one selected from SEQ ID NO:28, SEQ ID NO:57, and 62-74, or a fragment or variant thereof. In some embodiments, the polypeptide has at least 75% identity to any one selected from SEQ ID NO:28, SEQ ID NO:57, and 62-74, or a fragment or variant thereof. In some embodiments, the polypeptide has at least 80% identity to any one selected from SEQ ID NO:28, SEQ ID NO:57, and 62-74, or a fragment or variant thereof. In some embodiments, the polypeptide has at least 85% identity to any one selected from SEQ ID NO:28, SEQ ID NO:57, and 62-74, or a fragment or variant thereof. In some embodiments, the polypeptide has at least 90% identity to any one selected from SEQ ID NO:28, SEQ ID NO:57, and 62-74, or a fragment or variant thereof. In some embodiments, the polypeptide has at least 95% identity to any one selected from SEQ ID NO:28, SEQ ID NO:57, and 62-74, or a fragment or variant thereof. In some embodiments, the polypeptide has at least 96%, at least 97%, at least 98%, or at least 99% identity to any one selected from SEQ ID NO: 28, SEQ ID NO: 57, and 62-74, or a fragment or variant thereof. In some embodiments, the polypeptide is or comprises any one amino acid sequence selected from SEQ ID NO: 28, SEQ ID NO: 57, and 62-74, or a fragment or variant thereof. In some embodiments, the polypeptide is the polypeptide of any one of SEQ ID NO: 28, SEQ ID NO: 57, and 62-74. In some embodiments, the polypeptide is the polypeptide of any one of SEQ ID NO: 28, SEQ ID NO: 57, and 62-74. In some embodiments, the polypeptide is the polypeptide of SEQ ID NO: 28.

[0279] In another aspect, there is provided an artificial polypeptide of formula (VI) or (VII), or a variant of an artificial polypeptide of (I), (II), (III), (IV) or (V), for use in therapy.

[0280] In another aspect, there is provided an artificial polypeptide of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a variant of an artificial polypeptide of (I), (II), (III), (IV) or (V), for use in treating or preventing pain in a subject in need thereof.

[0281] In another aspect, there is provided a polypeptide having at least 70% identity to any one selected from SEQ ID NO: 28, SEQ ID NO: 57, and 62-74, or a fragment or variant thereof, for use in treating or preventing peripheral neuropathic pain in a subject in need thereof.

[0282] In another aspect, there is provided the use of an artificial polypeptide of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a variant of an artificial polypeptide of (I), (II), (III), (IV) or (V), for the preparation of a medicament for treating or preventing pain in a subject in need thereof.

[0283] In another aspect, there is provided use of a polypeptide having at least 70% identity to any one selected from SEQ ID NO: 28, SEQ ID NO: 57, and SEQ ID NO: 62-74, or a fragment or variant thereof, for the preparation of a medicament for treating or preventing peripheral neuropathic pain in a subject in need thereof.

[0284] In some embodiments, the medicament is for use in humans.

[0285] In some embodiments, the medicine is a veterinary medicine.

[0286] In some embodiments, a polypeptide or variant of the present disclosure, such as an artificial polypeptide of Formula (I), (II), (III), (IV), (V), (VI), or (VII), or a variant of an artificial polypeptide of Formula (I), (II), (III), (IV), or (V), or a polypeptide having at least 70% identity (e.g., at least 80% identity) to any one selected from SEQ ID NO: 28, SEQ ID NO: 57, and SEQ ID NOs: 62-74, or a fragment or variant thereof, can exhibit excellent analgesic effects and / or significantly improve the pain threshold of an animal, as evidenced by multiple pain-related models provided in the Examples (i.e., cancer pain associated with the HFD (high-fat diet) + STZ (streptozocin) model, the VZV (varicella-zoster virus) model, the SNL (spinal nerve ligation) model, the Walker 256 breast cancer cell-induced bone pain model, and the chemotherapy-induced peripheral neuropathy model).

[0287] In some embodiments, treatment with a polypeptide or variant of the disclosure, e.g., an artificial polypeptide of Formula (I), (II), (III), (IV), (V), (VI) or (VII), or a variant of an artificial polypeptide of Formula (I), (II), (III), (IV) or (V), or a polypeptide having at least 70% identity (e.g., at least 80% identity) to any one selected from SEQ ID NO: 28, SEQ ID NOs: 57, and 62-74, or a fragment or variant thereof, results in relief or reduction of pain in a subject. In some embodiments, after administration of an effective amount of a polypeptide or variant of the present disclosure to a subject, the severity or duration of the subject's pain is reduced by about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, after administration of an effective amount of a polypeptide or variant of the present disclosure to a subject, the severity or duration of the subject's pain is reduced by about 2-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 55-fold, about 60-fold, about 65-fold, about 70-fold, about 75-fold, about 80-fold, about 85-fold, about 90-fold, about 95-fold, about 100-fold or more.

[0288] In some embodiments, treatment with a polypeptide or variant of the disclosure, e.g., an artificial polypeptide of Formula (I), (II), (III), (IV), (V), (VI) or (VII), or a variant of an artificial polypeptide of Formula (I), (II), (III), (IV) or (V), or a polypeptide having at least 70% identity (e.g., at least 80% identity) to any one selected from SEQ ID NO: 28, SEQ ID NOs: 57, and 62-74, or a fragment or variant thereof, results in an increase or enhancement of pain threshold in a subject. In some embodiments, after administration of an effective amount of a polypeptide or variant of the present disclosure to a subject, the subject's pain threshold is increased or enhanced by about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, after administration of an effective amount of a polypeptide or variant of the present disclosure to a subject, the subject's pain threshold is increased or enhanced by about 2-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 55-fold, about 60-fold, about 65-fold, about 70-fold, about 75-fold, about 80-fold, about 85-fold, about 90-fold, about 95-fold, about 100-fold or more.

[0289] In some embodiments, treatment comprises administering to a subject an effective amount of a polypeptide or variant of the present disclosure. In some embodiments, the effective amount of a polypeptide or variant of the present disclosure is from about 0.01 μg to about 1000 mg. In some embodiments, the effective amount of a polypeptide or variant of the present disclosure is at least 0.01 μg, 0.02 μg, 0.05 μg, 0.1 μg, 0.2 μg, 0.5 μg, 1 μg, 2 μg, 5 μg, 10 μg, 50 μg, 100 μg, 200 μg, 500 μg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg. In some embodiments, an effective amount of a polypeptide or variant of the disclosure is at most 0.01 μg, 0.02 μg, 0.05 μg, 0.1 μg, 0.2 μg, 0.5 μg, 1 μg, 2 μg, 5 μg, 10 μg, 50 μg, 100 μg, 200 μg, 500 μg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg. In some embodiments, an effective amount of a polypeptide or variant of the disclosure is from about 0.01 μg / kg to about 100 mg / kg. In some embodiments, an effective amount of a polypeptide or variant of the disclosure is at least 0.01 μg / kg, 0.02 μg / kg, 0.05 μg / kg, 0.1 μg / kg, 0.2 μg / kg, 0.5 μg / kg, 1 μg / kg, 2 μg / kg, 5 μg / kg, 10 μg / kg, 50 μg / kg, 100 μg / kg, 200 μg / kg, 500 μg / kg, 1 mg / kg, 2 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, 50 mg / kg, or 100 mg / kg.In some embodiments, the effective amount of a polypeptide or variant of the disclosure is at most 0.01 μg / kg, 0.02 μg / kg, 0.05 μg / kg, 0.1 μg / kg, 0.2 μg / kg, 0.5 μg / kg, 1 μg / kg, 2 μg / kg, 5 μg / kg, 10 μg / kg, 50 μg / kg, 100 μg / kg, 200 μg / kg, 500 μg / kg, 1 mg / kg, 2 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, 50 mg / kg, or 100 mg / kg.

[0290] In some embodiments, the method comprises administering an effective amount of a polypeptide or variant of the present disclosure to the subject once daily. In some embodiments, the method comprises administering an effective amount of a polypeptide or variant of the present disclosure to the subject twice daily. In some embodiments, the method comprises administering an effective amount of a polypeptide or variant of the present disclosure to the subject three or more times daily. In some embodiments, the method comprises administering an effective amount of a polypeptide or variant of the present disclosure to the subject every two days. In some embodiments, the method comprises administering an effective amount of a polypeptide or variant of the present disclosure to the subject every three days. In some embodiments, the method comprises administering an effective amount of a polypeptide or variant of the present disclosure to the subject weekly. In some embodiments, the method comprises administering an effective amount of a polypeptide or variant of the present disclosure to the subject every two weeks. In some embodiments, the method comprises administering an effective amount of a polypeptide or variant of the present disclosure to the subject monthly.

[0291] In some embodiments, the pain is at least one selected from the group consisting of acute pain, chronic pain, and transitional pain.

[0292] In some embodiments, the acute pain is at least one selected from the group consisting of pain associated with an acute injury, acute inflammatory pain, and headache.

[0293] In some embodiments, the pain associated with an acute injury is acute post-operative pain.

[0294] In some embodiments, the chronic pain is at least one selected from the group consisting of nociceptive pain, neuropathic pain, and mixed pain.

[0295] In some embodiments, the nociceptive pain is at least one selected from the group consisting of abdominal pain, anal fissure pain, bladder pain, complex regional pain syndrome, breast pain, intestinal spasm, bladder pain syndrome, joint pain, musculoskeletal pain, muscle pain, myofascial pain syndrome, nociceptive bone pain, pain associated with pancreatitis, polymyalgia rheumatica, chronic post-operative pain, renal pain, somatic pain, tendon pain, ligament pain, chronic traumatic pain, pain associated with fractures, and visceral pain.

[0296] In some embodiments, the breast pain is cyclical breast pain.

[0297] In some embodiments, the renal pain is renal colic.

[0298] In some embodiments, the pain associated with a fracture is pain associated with a spinal fracture.

[0299] In some embodiments, the mixed pain is at least one selected from the group consisting of arthritis pain, back pain, cancer pain, dental pain, fibromyalgia, chronic inflammatory pain, lower back pain, neck pain, and eye pain.

[0300] In some embodiments, the arthritis pain is at least one selected from the group consisting of osteoarthritis pain, rheumatoid arthritis pain, and gout pain.

[0301] In some embodiments, the cancer pain is tumor-associated cancer pain.

[0302] In some embodiments, the tumor-associated cancer pain is at least one selected from the group consisting of cancer-associated nerve pain, cancer-associated bone pain, cancer-associated soft tissue pain, and cancer-associated referred pain.

[0303] In some embodiments, the cancer-associated bone pain is at least one selected from the group consisting of bone pain associated with bone cancer and bone pain associated with bone metastatic tumors.

[0304] In some embodiments, the bone pain associated with bone cancer is at least one selected from the group consisting of bone pain associated with chondrosarcoma, bone pain associated with Ewing's sarcoma, bone pain associated with malignant fibrous histiocytoma of bone, bone pain associated with osteosarcoma, and bone pain associated with fibrochondromeschymoma of bone.

[0305] In some embodiments, the cancer pain is cancer pain associated with a diagnostic and / or therapeutic procedure.

[0306] In some embodiments, the cancer pain associated with a diagnostic and / or therapeutic procedure is cancer-associated phantom pain. In some embodiments, the cancer pain associated with a diagnostic and / or therapeutic procedure is chemotherapy-associated cancer pain. In some embodiments, the chemotherapy-associated cancer pain is cancer pain associated with chemotherapy-induced peripheral neuropathy (CIPN). In some embodiments, the chemotherapy is administered by administering a cytotoxic agent to a subject in need thereof. In some embodiments, the cytotoxic agent is at least one selected from the group consisting of platinum anticancer agents (e.g., cisplatin, carboplatin, nedaplatin, and oxaliplatin), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), taxanes (e.g., paclitaxel and docetaxel), and proteasome or angiogenesis inhibitors (e.g., bortezomib, carfilzomib, and thalidomide).

[0307] In some embodiments, the ocular pain is at least one selected from the group consisting of ocular nociceptive pain and ocular neuropathic pain.

[0308] In some embodiments, the ocular nociceptive pain is at least one selected from the group consisting of eye pain associated with injury, eye pain associated with surgery, eye pain associated with contact lens wear, and eye pain associated with the irritation of a foreign body.

[0309] In some embodiments, the ocular neuropathic pain is at least one selected from the group consisting of allergy-related ocular pain, infection-related ocular pain, inflammation-related ocular pain, chronic ocular surface disease-related ocular pain, postoperative ocular neuropathic pain, toxic keratopathy-related ocular pain, radiation-related ocular pain, ultraviolet light exposure-related ocular pain, systemic neuropathy-related ocular pain, traumatic ocular neuropathic pain, trigeminal neuralgia-related ocular pain, and fibromyalgia-related ocular pain. In some embodiments, the infection is at least one selected from the group consisting of herpes simplex keratitis and herpes zoster keratitis. In some embodiments, the chronic ocular surface disease is at least one selected from the group consisting of dry eye syndrome, recurrent corneal erosion, chemical burns, and ocular surface neoplasia. In some embodiments, the surgery causing postoperative ocular neuropathic pain is at least one selected from the group consisting of corneal refractive surgery, cataract surgery, and corneal transplant surgery. In some embodiments, the toxic keratopathy is localized toxic keratopathy, such as localized toxic keratopathy associated with preservatives containing benzalokium chloride, or systemic toxic keratopathy, such as systemic toxic keratopathy associated with isotretinoin. In some embodiments, the systemic neuropathy is at least one selected from the group consisting of diabetes, small fiber neuropathy, and multiple sclerosis.

[0310] In some embodiments, the ophthalmic neuropathic pain is at least one selected from the group consisting of corneal neuralgia, conjunctival neuralgia, optic nerve neuralgia, extraocular neuralgia, orbital neuralgia, and palpebral neuralgia.

[0311] In some embodiments, the neuropathic pain is at least one selected from the group consisting of central neuropathic pain and peripheral neuropathic pain.

[0312] In some embodiments, the central neuropathic pain is at least one selected from the group consisting of post-stroke neuropathic pain, syringomyelia pain, neuropathic pain associated with ischemic myelopathy, neuropathic pain associated with compressive myelopathy, neuropathic pain associated with radiation myelopathy, neuropathic pain associated with spinal cord injury, neuropathic pain associated with multiple sclerosis, neuropathic pain associated with Parkinson's disease, phantom limb pain, and neuropathic pain associated with myelitis.

[0313] In some embodiments, the peripheral neuropathic pain is at least one selected from the group consisting of peripheral neuropathic pain associated with metabolic disorders or ischemia, peripheral neuropathic pain associated with infection, peripheral neuropathic pain associated with nerve or nerve root compression, peripheral neuropathic pain associated with chemotherapy, peripheral neuropathic pain associated with radiation therapy, stump pain, peripheral neuropathic pain associated with neuropathy due to tumor compression or infiltration, peripheral neuropathic pain associated with alcoholic polyneuropathy, peripheral neuropathic pain associated with nutritional neuropathy, peripheral neuropathic pain associated with toxic peripheral neuropathy, and peripheral neuropathic pain associated with immune-mediated neuropathy.

[0314] In some embodiments, the peripheral neuropathic pain associated with a metabolic disorder or ischemia is at least one selected from the group consisting of diabetic peripheral neuropathic pain and ischemic peripheral neuropathic pain.

[0315] In some embodiments, the peripheral neuropathic pain associated with an infection is at least one selected from the group consisting of peripheral neuropathic pain associated with a viral infection and peripheral neuropathic pain associated with a spirochete infection.

[0316] In some embodiments, the peripheral neuropathic pain associated with a viral infection is at least one selected from the group consisting of postherpetic neuralgia and peripheral neuropathic pain associated with HIV infection.

[0317] In some embodiments, the peripheral neuropathic pain associated with a spirochete infection is peripheral neuropathic pain associated with a syphilis infection.

[0318] In some embodiments, the peripheral neuropathic pain associated with compression of a nerve or nerve root is at least one selected from the group consisting of sciatica, trigeminal neuralgia, glossopharyngeal neuralgia, neuropathic pain associated with radiculoneuropathy, and neuropathic pain associated with entrapment neuropathy.

[0319] In some embodiments, the subject is a mammal. In some embodiments, the subject is any one selected from the group consisting of humans, primates, rodents, dogs, cats, horses, sheep, and pigs. In some embodiments, the subject is a human. In some embodiments, the subject is an infant, toddler, child, adolescent, adult, or elderly. In some embodiments, the subject is a male or female. In some embodiments, the subject is a pet. In some embodiments, the subject is any one selected from the group consisting of fish, frogs, salamanders, reptiles (e.g., turtles, lizards, snakes, and iguanas), birds (e.g., parrots), mice, rats, guinea pigs, gerbils, hamsters, chinchillas, rabbits, ferrets, cats, dogs, and pigs.

[0320] In some embodiments, a polypeptide or variant of the present disclosure, e.g., an artificial polypeptide of Formula (I), (II), (III), (IV), (V), (VI) or (VII), or a variant of an artificial polypeptide of Formula (I), (II), (III), (IV) or (V), or a polypeptide having at least 70% identity (e.g., at least 80% identity) to any one selected from SEQ ID NO: 28, SEQ ID NOs: 57, and 62-74, or a fragment or variant thereof, is administered in the form of a formulation comprising a polypeptide or variant of the present disclosure and a pharmaceutically acceptable excipient.

[0321] In some embodiments, the formulation is in a form suitable for oral administration, hi some embodiments, the formulation is in the form of a tablet, capsule, pill, powder, granule, liquid, suspension, or emulsion.

[0322] In some embodiments, the formulation is in a form suitable for parenteral administration, ie, in the form of a sterile injectable solution, suspension, emulsion, gel (e.g., injectable hydrogel), or sterile powder.

[0323] In some embodiments, the formulation is in a form suitable for topical administration, ie, in the form of a spray, aerosol, inhalable powder, ointment, cream, patch, suppository, paste, film, or gel.

[0324] In some embodiments, the formulation is in the form of a sustained-release, controlled-release, or delayed-release formulation. In some embodiments, the formulation is in the form of a matrix tablet, a compressed tablet with mixed particles having different release rates, an osmotic pump tablet, a sustained- or controlled-release capsule or microcapsule, a sustained- or controlled-release implant, a sustained- or controlled-release granule, a microparticle or microsphere, an enteric-coated capsule or tablet, a colonic placement formulation, a gel (e.g., a hydrogel), a liposomal formulation, an ion-exchange resin formulation, a floating formulation, a bioadhesive formulation, a stimulant-triggered release formulation, and a pulsatile drug delivery system.

[0325] In some embodiments, the formulation is for use in humans.

[0326] In some embodiments, the formulation is a veterinary formulation.

[0327] Further details of these formulations are provided above in the section entitled "Formulations."

[0328] Preparation of Polypeptides Polypeptides or variants of the present disclosure, such as artificial polypeptides of Formula (I), (II), (III), (IV), (V), (VI) or (VII), or variants of artificial polypeptides of Formula (I), (II), (III), (IV) or (V), or polypeptides having at least 70% identity (e.g., at least 80% identity) to any one selected from SEQ ID NO: 28, SEQ ID NOs: 57, and 62-74, or fragments or variants thereof, can be prepared by any suitable method, including, but not limited to, molecular cloning techniques and synthetic procedures. Standard molecular cloning techniques are well known in the art and are described by Sambrook, J., Fritsch, E. F. and Maniatis, T. Molecular Cloning: A Laboratory Manual; Cold Spring Harbor Laboratory Press: Cold Spring Harbor, (1989) (Maniatis), and by T. J. Silhavy, M. L. Bennan, and L. W. Enquist Experiments with Gene Fusions, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (1984), and by Ausubel, F. M. et al., Current Protocols in Molecular Biology, pub. by Greene Publishing Assoc. and Wiley-Interscience (1987).

[0329] In some embodiments, the polypeptide or variant of the present disclosure is prepared by referring to the fermentation-based production method disclosed in Chinese Patent Application No. 201711320516.4 (Publication No.: CN109913483), the entire contents of which are incorporated herein by reference. In some embodiments, the method for preparing the polypeptide or variant of the present disclosure includes the steps of: incorporating a target gene fragment into an expression plasmid by genetic engineering, wherein the incorporated target gene fragment contains at least one purification tag; transforming the expression plasmid into a corresponding expression host to construct a recombinantly engineered cell that highly expresses the target polypeptide; subjecting the recombinantly engineered cell to fermentation, induced expression, and then crude purification to obtain a crude polypeptide; and subjecting the crude polypeptide to precision purification to obtain a highly purified polypeptide.

[0330] In some embodiments, the target gene fragment is any one selected from the group consisting of a gene fragment capable of encoding a polypeptide or variant of the present disclosure, such as an artificial polypeptide of Formula (I), (II), (III), (IV), (V), (VI), or (VII), or a variant of an artificial polypeptide of Formula (I), (II), (III), (IV), or (V), or a polypeptide or fragment or variant thereof having at least 70% identity (e.g., at least 80% identity) to any one selected from SEQ ID NO: 28, SEQ ID NO: 57, and SEQ ID NOs: 62-74. In some embodiments, the target gene fragment is a gene fragment capable of encoding an artificial polypeptide of Formula (I), (II), (III), (IV), (V), (VI), or (VII). In some embodiments, the target gene fragment is a gene fragment capable of encoding a variant of an artificial polypeptide of Formula (I), (II), (III), (IV), or (V). In some embodiments, the target gene fragment is a gene fragment capable of encoding a polypeptide having at least 70% identity (e.g., at least 80% identity) to any one selected from SEQ ID NO: 28, SEQ ID NO: 57, and SEQ ID NO: 62-74, or a fragment or variant thereof. The target gene fragment may be prepared by any suitable method, including, but not limited to, enzymatic synthesis, i.e., synthesizing cDNA by reverse transcription using RNA as a template, and chemical synthesis, i.e., synthesizing the target gene using chemical methods or chemical methods in combination with enzymatic methods. Preparation of the target gene fragment may also be performed commercially by a contract research organization (CRO) if the sequence of the target gene fragment is provided.

[0331] In some embodiments, the purification tag is an ST sequence tag (an amino acid sequence that helps a polypeptide or variant of the disclosure form inclusion bodies) or a His tag.

[0332] In some embodiments, the expression host is a host cell. A host cell includes, but is not limited to, an individual cell, a cell culture, or a cell line. In some embodiments, a host cell includes the progeny of a single host cell. In some embodiments, a host cell can be transfected with a heterologous sequence, including a vector encoding a polypeptide or variant of the present disclosure. In some embodiments, the host cell can be a prokaryotic cell, such as a bacterial cell. In some embodiments, the host cell can be a eukaryotic cell, such as a yeast cell, an animal cell, an insect cell, or a plant cell.

[0333] Examples of bacterial host cells that can be used to produce the polypeptides or variants of the present disclosure include microorganisms belonging to the genera Escherichia, Serratia, Bacillus, Brevibacterium, Corynebacterium, Microbacterium, Pseudomonas, etc. For example, bacterial host cells can include, but are not limited to, Escherichia coli XL1-Blue, XL2-Blue, DH1, MC1000, KY3276, W1485, JM109, HB101, No. 49, iW3110, NY49, G1698, BL21, or TB1.Other bacterial host cells include Serratia ficaria, Serratia fonticola, Serratia liquefaciens, Serratia marcescens, Bacillus subtilis, Bacillus amyloliquefaciens, Brevibacterium ammoniagenes, Brevibacterium immariophilum ATCC 14068, Brevibacterium saccharolyticum ATCC 14066, Brevibacterium flavum ATCC 14068, and Brevibacterium saccharolyticum ATCC 14068. 14067, Brevibacterium lactofermentum ATCC 13869, Corynebacterium glutamicum ATCC 13032, Corynebacterium glutamicum ATCC 13869, Corynebacterium acetoacidophilum ATCC 13870, Microbacterium ammoniaphilum ATCC 15354, Pseudomonas putida, Pseudomonas sp. D-0110, and the like.

[0334] Examples of yeast cells that can be used to produce the polypeptides or variants of the present disclosure include, for example, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces lactis, Trichosporon pullulans, Schwanniomyces alluvius, Candida utilis, and the like. utilis, and the like, including microorganisms belonging to the genera Kluyveromyces, Trichosporon, Saccharomyces, Schizosaccharomyces, Schwanniomyces, Pichia, Candida, and the like.

[0335] Examples of animal cells that can be used to produce the polypeptides or variants of the present disclosure include mammalian cells, e.g., monkey cells such as Chinese hamster ovary cells (CHO) or COS cells, HepG2 cells, A549 cells, and any other cells available through the ATCC or other depository institution.

[0336] In some embodiments, the expression host is an E. coli host cell. In some embodiments, the composition of the fermentation medium used in the fermentation process may be: yeast extract powder 10-50 g / L, peptone 10-30 g / L, ammonium sulfate 2-10 g / L, sodium chloride 2-10 g / L, potassium dihydrogen phosphate 0-10 g / L, dipotassium hydrogen phosphate 2-15 g / L, antifoaming agent 0.01-0.1% (v / v), FeSO4·7H2O 0-0.1 g / L, ZnSO4·7H2O 0-0.02 g / L, CuSO4·5H2O 0-0.1 g / L, MnSO4·5H2O 0-0.05 g / L, CaCl2·7H2O 0-0.01 g / L, CoCl2·6H2O 0-0.01 g / L, Na2MoO4·2H2O In some embodiments, the fermentation process is carried out at 37°C.

[0337] In some embodiments, inducible expression is achieved by the addition of isopropyl-β-D-thiogalactopyranoside (IPTG) during the fermentation process. In some embodiments, IPTG is added 0.5, 1, 2, 3, 4, or 5 hours after the start of the fermentation process. In some embodiments, IPTG is added to a final concentration of 0.25, 0.5, 1, 2, or 4 mM. In some embodiments, inducible expression is performed at 37°C.

[0338] The crude purification of the present disclosure is a process in which the culture produced by the fermentation process is preliminarily treated during the process.In some embodiments, crude purification includes the steps of collecting cells, lysing the cells, and then isolating inclusion body proteins and / or cytoplasmic proteins; subjecting the inclusion body proteins and / or cytoplasmic proteins to denaturation, renaturation, and enzymatic digestion to obtain a crude product containing crude polypeptide.In some embodiments, crude purification includes the steps of collecting the culture medium, removing cells and impurities, and obtaining a supernatant, i.e., a crude product containing crude polypeptide.

[0339] The refinement of the present disclosure is the process that the crude product containing crude polypeptide is purified by chromatography during that time.The example of the chromatography method that can be used to purify the polypeptide or variant of the present disclosure includes: ion exchange chromatography using strong anion exchange resin, weak anion exchange resin or multimode anion exchange resin; affinity chromatography; reversed-phase chromatography using reversed-phase packing material; molecular sieve chromatography using size-exclusion packing material; and hydrophobic chromatography using hydrophobic packing material.

[0340] More detailed information for preparing the polypeptides of the present disclosure can be found throughout the disclosure of Chinese Patent No. 109913483, for example, through Examples 1-4.

[0341] kit The present disclosure also provides a kit for treating or preventing pain, for example, peripheral neuropathic pain, in a subject who needs to treat or prevent pain, for example, peripheral neuropathic pain.In some embodiments, the kit comprises one or more of the polypeptides or variants of the present disclosure and instructions for using the kit.In some embodiments, the kit comprises one or more of the formulations described herein and instructions for using the kit.

[0342] The kit can include one or more containers containing one or more of the polypeptides or variants of the present disclosure or formulations comprising them. The polypeptides or variants of the present disclosure can be present in the container as a prepared formulation, or the polypeptides or variants of the present disclosure can be unformulated. In some embodiments, the kit can include an unformulated polypeptide or variant of the present disclosure in a container separate from a pharmaceutically acceptable excipient. Prior to use, the polypeptides of the present disclosure are diluted or otherwise mixed with a pharmaceutically acceptable excipient.

[0343] In some embodiments, the kits provided herein also include instructions describing how to administer the formulation. In some embodiments, the instructions also describe the procedure for mixing the polypeptide or variant of the present disclosure contained in the kit with a pharmaceutically acceptable excipient.

[0344] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. The present invention is not intended to be limited by the specific examples provided herein. While the present invention has been described with reference to the above specification, the descriptions and illustrations of the embodiments herein are not intended to be construed in a limiting sense. Those skilled in the art will now envision numerous variations, changes, and substitutions without departing from the invention. Furthermore, it should be understood that all aspects of the present invention are not limited to the specific descriptions, configurations, or relative proportions set forth herein, which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be used in practicing the invention. It is therefore contemplated that the present invention shall encompass any such alternatives, modifications, variations, or equivalents. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be embraced thereby. [Example]

[0345] Example The present disclosure will now be described with reference to the following examples, which are intended to illustrate but not limit the invention.

[0346] Unless otherwise specified, unless specific conditions are given in the examples, the examples are carried out according to conventional conditions or conditions suggested by the manufacturer. Reagents or equipment used without manufacturer's instructions are commercially available, conventional products. Those skilled in the art will understand that the examples described herein are not intended to limit the scope of the invention as claimed.

[0347] Example 1: Effect of polypeptides of the present disclosure administered via subcutaneous route on the treatment of VZV-induced pain model in rats In this example, the effect of an exemplary polypeptide of the present disclosure, i.e., SEQ ID NO: 29, administered via the subcutaneous (sc) route on the treatment of pain was investigated in a VZV (varicella zoster virus)-induced pain model in rats.

[0348] Modeling

[0349] A summary of the method for inducing the pain model in rats by subcutaneous VZV inoculation is provided below. Briefly, Zoletil 登録商標 Male Sprague Dawley (SD) rats were deeply anesthetized by intraperitoneal injection of 50 (30 mg / kg) / xylazine (6 mg / kg) anesthetic at an injection volume of 6 mL / kg, and then inoculated with virus by subcutaneous injection in the footpad region. The infectious dose was 22,800 TCID50 per animal, and the infection volume was 150 μL for all rats.

[0350] Grouping and administration

[0351] Rats were randomized into two groups: 8 rats in the placebo group (Group 1, administered vehicle (saline)) and 8 rats in the treatment group (Group 2, administered SEQ ID NO: 29).

[0352] Administration was performed every other day. Briefly, the test substance was administered by subcutaneous injection in the footpad region on days 1 and 3, respectively. For Group 2, administration of SEQ ID NO: 29 began at the first concentration: the first concentration (10 μg / mL) was administered on day 1, and the second concentration (20 μg / mL) was administered on day 3. Pain was measured once after each administration.

[0353] More detailed information about the studies is shown in Table 1.

[0354] [Table 1]

[0355] pain measurement

[0356] One hour after administration of the test substance on days 1 and 3, the rats were subjected to a mechanical allodynia test (also known as the "von Frey test") to measure pain. In behavioral tests on rats, mechanical allodynia was measured using the following formula: 50%PWT(g)=(10^(Xf+kδ)) / 10,000 (In the formula, Xf = final test fiber value used in the test k = tabulated value for the pattern of positive / negative responses (Chaplan et al. 1994, page 62) δ=average difference) The mean paw withdrawal threshold (PWT) is expressed as 50% calculated according to the following:

[0357] Briefly, rats were individually placed in a Plexiglas box with a grid on the bottom to ensure reliable testing of their paws. Rats were allowed to acclimate to the environment for 15 minutes before testing. After acclimation was complete, rats were tested for pain (mechanical allodynia) in the mid-plantar region of their left hind paw using test fibers. Test fibers included eight test strengths: 3.61 (0.4 g), 3.84 (0.6 g), 4.08 (1 g), 4.31 (2 g), 4.56 (4 g), 4.74 (6 g), 4.93 (8 g), and 5.18 (15 g). During testing, the test fiber was pressed perpendicular to the skin, and force was applied to flex the fiber for 6–8 seconds, with a 5-second interval between each test. Pain responses were recorded if the animal rapidly retracted its paw during testing. Pain responses were also recorded if the animal retracted its paw as the test fiber left the animal's skin. If the animal moves or walks around, no pain response is recorded and the test should be repeated. The test started at 4.31 (2 g). If the animal has a pain response, the next test should be performed using a test fiber with a lower strength; if the animal does not have a pain response, the next test should be performed using a test fiber with a higher strength. The maximum strength of the fiber tested was 5.18 (15 g). The test results were recorded in a table, with the presence of a pain response recorded as "x" and the absence of a pain response recorded as "o." An exemplary table for use in mechanical allodynia testing is shown below in Table 2.

[0358] [Table 2]

[0359] result

[0360] 1 shows the 50% PWT values ​​of rats from both the placebo group and the treatment group (various concentrations of SEQ ID NO: 29, subcutaneous, single administration) obtained from the mechanical allodynia test in Example 1. It can be seen from FIG. 1 that the polypeptide of the present disclosure administered via the subcutaneous route exhibited obvious analgesic effects on the VZV-induced pain model in rats, and subcutaneous administration of polypeptide SEQ ID NO: 29 increased the 50% PWT values ​​of rats in a dose-dependent manner.

[0361] Example 2: Effect of polypeptides of the present disclosure administered via intravenous route on the treatment of VZV-induced pain model in rats In this example, the effect of an exemplary polypeptide of the present disclosure, namely SEQ ID NO: 29, administered via the intravenous (iv) route on the treatment of pain was investigated in a VZV-induced pain model in rats.

[0362] Modeling

[0363] Modeling was performed according to the method described in Example 1.

[0364] Grouping and administration

[0365] Rats were randomly divided into two groups: 8 rats in the placebo group (Group 1, administered vehicle (saline)) and 8 rats in the treatment group (Group 2, administered 30 mg of SEQ ID NO: 29 / kg). Briefly, rats were administered the test article by intravenous injection on one day.

[0366] pain measurement

[0367] According to the method described in Example 1, the rats were subjected to a mechanical allodynia test 0.5 hours after administration of the test substance.

[0368] result

[0369] 1 also shows the 50% PWT values ​​of rats from both the placebo group and the treatment group (30 mg SEQ ID NO: 29 / kg, intravenously, single dose) obtained from the mechanical allodynia test in Example 2. From FIG. 1, it can be seen that the polypeptide of the present disclosure administered via the intravenous route exhibited obvious analgesic effects on the VZV-induced pain model in rats, and intravenous administration of polypeptide SEQ ID NO: 29 significantly increased the 50% PWT values ​​of rats.

[0370] Example 3: Effect of various polypeptides of the present disclosure administered via intravenous route on the treatment of VZV-induced pain model in rats In this example, the effect of various polypeptides of the present disclosure administered via the intravenous route on the treatment of pain was examined in a VZV-induced pain model in rats.

[0371] Modeling

[0372] Modeling was performed according to the method described in Example 1.

[0373] Grouping and administration

[0374] Rats were randomly divided into three groups: 8 rats in the placebo group (Group 1, administered vehicle (saline)) and 16 rats in the treatment groups (Groups 2 and 3, 8 rats / group, administered various polypeptides). Briefly, vehicle (saline) was administered to rats in Group 1, and various polypeptides were administered to rats in Groups 2 (SEQ ID NO:29, SEQ ID NO:57, and SEQ ID NO:49; 10 mg polypeptide / kg) and 3 (SEQ ID NO:75 and SEQ ID NO:28; 10 mg polypeptide / kg) on ​​one day via intravenous injection. More detailed information about the study is shown in Table 3.

[0375] [Table 3]

[0376] NOTE: For animals in groups 2 and 3, administration of the different polypeptides, respectively, was separated by a washout period (approximately 2-3 days apart).

[0377] pain measurement

[0378] According to the method described in Example 1, the rats were subjected to a mechanical allodynia test 0.5 hours after administration of the test substance.

[0379] result

[0380] Figure 1 also shows the 50% PWT values ​​of rats from both the placebo and treatment groups (10 mg polypeptide / kg, intravenously, single dose) obtained from the mechanical allodynia test in Example 3. From Figure 1, it can be seen that various polypeptides of the present disclosure, including SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:49, SEQ ID NO:57, and SEQ ID NO:75, administered via the intravenous route, showed obvious analgesic effects on the VZV-induced pain model in rats.

[0381] Example 4: Effect of various polypeptides of the present disclosure administered via intravenous route on the treatment of HFD+STZ-induced pain model in mice In this example, the effect of various polypeptides of the present disclosure administered via the intravenous route on the treatment of pain was investigated in a high fat diet (HFD) + STZ (streptozocin)-induced pain model in mice.

[0382] Modeling

[0383] The following provides an overview of the method for inducing the pain model in mice by high-fat diet plus STZ injection. Briefly, C57BL / 6 mice were fed a high-fat diet (HFD) for 4 weeks, and after 4 weeks of HFD feeding, STZ (100 mg / kg) was injected intraperitoneally once, followed by an additional 4 weeks of continuous HFD feeding. Fasting was required for 6 hours before and 2 hours after STZ injection, respectively. Blood glucose testing was performed one week after STZ injection (fasting for more than 12 hours before testing was required). Blood glucose testing was performed 4 weeks after STZ injection, and then the mice were divided into groups.

[0384] Grouping, Dosing and Pain Measurement

[0385] Briefly, after modeling, a total of 20 model mice were randomly divided into two groups (10 rats per group) according to blood glucose level.Various polypeptides of the present disclosure (SEQ ID NO:28, 29, 57, 86, 89, 90, 91, 93, 94, 95, 104, 106, 107, 108, 109 and 110) were administered to mice according to the following protocol (20mg / kg, intravenous, single administration): Group 1: SEQ ID NO:28, SEQ ID NO:57, SEQ ID NO:104, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109 and SEQ ID NO:110; and Group 2: SEQ ID NO:29, SEQ ID NO:86, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:94 and SEQ ID NO:95. Mice were subjected to mechanical allodynia testing before and 1 hour after administration according to a method similar to that described in Example 1, but with slight modifications (the test strengths of the test fibers were instead 2.36 (0.02 g), 2.44 (0.04 g), 2.83 (0.07 g), 3.22 (0.16 g), 3.61 (0.4 g), 3.84 (0.6 g), 4.08 (1 g), 4.17 (1.4 g), with a starting test strength of 3.22 (0.16 g). More detailed information about the study is shown in Table 4.

[0386] [Table 4]

[0387] NOTE: For animals in groups 1 and 2, administration of the different polypeptides, respectively, was separated by a washout period (approximately 3-5 days apart).

[0388] result

[0389] 2 shows the 50% PWT values ​​of mice from various treatment groups (20 mg polypeptide / kg, intravenously, single dose) obtained from the mechanical allodynia study in Example 4. From FIG. 2, various polypeptides of the present disclosure tested in this study, including SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:57, SEQ ID NO:104, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:86, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:94, and SEQ ID NO:95, when administered intravenously, exhibited an anti-inflammatory effect on the HFD+STZ-induced pain model in mice. It can be confirmed that the same analgesic effect was observed.

[0390] Example 5: Effect of various polypeptides of the present disclosure administered via intravenous route on the treatment of the SNL pain model in rats In this example, the effects of various polypeptides of the present disclosure on the treatment of pain were examined in the SNL (spinal nerve ligation) pain model in rats.

[0391] Modeling

[0392] A summary of the method for inducing a pain model in rats by spinal nerve ligation is provided below. Briefly, Zoletil 登録商標 Male SD rats were anesthetized with 50 mg xylazine hydrochloride (20 mg / kg + 8 mg / kg, intraperitoneal injection). The surgical site on the lumbar region of the animal was shaved, and the skin was disinfected three times with iodophor and 70% v / v ethanol. The left spinal nerves L5 and L6 of the animal were isolated and tightly ligated with 6-0 silk suture, and the wound was sutured.

[0393] On the 11th day after surgery, the animals were acclimatized to the experimental environment for 15 minutes per day for 3 consecutive days. On the 13th day after surgery, the baseline mechanical allodynia values ​​of the model rats were measured, and those that did not show mechanical allodynia (having a 50% PWT value of more than 5 g) were excluded. The animals were then randomly divided into various groups.

[0394] Grouping, Dosing and Pain Measurement

[0395] The study was divided into two parts, with a first group of 34 animals used in Part I of the study and a second group of another 30 animals used in Part II of the study. The Part I and Part II experiments were conducted separately.

[0396] Part I: Evaluation of the effect of a single intravenous administration of various doses of an exemplary polypeptide of the present disclosure, i.e., SEQ ID NO: 29, on the treatment of the SNL pain model in rats

[0397] Part I of this study was conducted according to the experimental details shown in Table 5.

[0398] [Table 5]

[0399] Briefly, after SNL modeling, 24 animals were randomly divided into three groups (Groups 2, 3, and 4, N=8 / group). Group 1 (Sham group, 10 animals underwent essentially the same surgical procedures as the other groups, but their left spinal nerves L5 and L6 were not isolated or ligated) was used as a control group. Test substances were administered to the animals according to the protocol shown in Table 5, and mechanical allodynia tests were performed one hour after administration according to the method described in Example 1.

[0400] Part II: Evaluation of the effect of a single intravenous administration of various polypeptides of the present disclosure on the treatment of the SNL pain model in rats

[0401] Part II of this study was conducted according to the experimental details shown in Table 6.

[0402] [Table 6]

[0403] Briefly, after SNL modeling, 30 animals were randomly divided into three groups (Group 1, N=6 / group; Groups 2 and 3, N=12 / group). Various polypeptides of the present disclosure were administered to animals from Groups 2 and 3, and the animals were subjected to a mechanical allodynia test one hour after administration according to the method described in Example 1.

[0404] result

[0405] Figure 3 shows the 50% PWT values ​​of mice from the sham group, vehicle group, and various treatment groups (SEQ ID NOs: 29, 90, and 93, intravenous, single administration) obtained from the mechanical allodynia test in Example 5. From Figure 3, it can be seen that the various polypeptides of the present disclosure tested in this study, including SEQ ID NO: 29, SEQ ID NO: 90, and SEQ ID NO: 93, have a certain analgesic effect on the SNL pain model in rats when administered intravenously. Furthermore, it was shown that the analgesic effect produced by a dose of 60 mg of SEQ ID NO: 29 / kg is much higher than that produced by a dose of 30 mg of SEQ ID NO: 29 / kg, suggesting a dose-dependent manner of the analgesic effect of the polypeptides of the present disclosure.

[0406] Example 6: Effect of polypeptides of the present disclosure administered via intravenous route on the treatment of Walker 256 breast cancer cell-induced bone pain model in rats Bone metastasis is considered to be one of the most common causes of pain in cancer patients. When transplanted into rats, Walker256 cells can cause significant bone resorption at the site of transplantation and increase skeletal fragility (Kurth et al., (2000). Treatment with ibandronate preserves bone in experimental tumor-induced bone loss. J. Bone Joint Surg. Br. 82, 126-130.), which is representative of the phenotype observed in breast cancer patients with bone metastasis (Shih et al., (2004). Bone resorption activity of osteolytic metastatic lung and breast cancers. J. Orthop. Res. 22, 1161-1167). Therefore, in this example, the effect of an exemplary polypeptide of the present disclosure, i.e., SEQ ID NO: 29, administered via intravenous (iv) route on pain treatment was examined in a rat model of bone pain induced by Walker256 breast cancer cells.

[0407] Grouping

[0408] Based on body weight, a total of 28 female Wistar rats were randomly divided into three groups: 8 rats in the sham group (Group 1, administered vehicle (saline)), 10 rats in the model group (Group 2, administered vehicle (saline)), and 10 rats in the treatment group (Group 3, administered 60 mg of SEQ ID NO: 29 / kg).

[0409] Modeling

[0410] A summary of the method for inducing a bone pain model in rats by intratibial injection of a suspension of Walker 256 breast cancer cells is provided below. Briefly, rats were anesthetized and then injected with 4 μL of a suspension of Walker 256 cancer cells (approximately 4×10 5 The rats were injected with a 1000-μL IgG4-containing medium containing 1000 μg / mL of IgG4-containing medium (containing 1000 μg / mL of IgG4-containing medium containing ...

[0411] Administration

[0412] After cancer cell injection (day 0), treatment began the next day (day 1) and was administered once daily for 14 consecutive days (days 1, 2, ... 14, respectively). More detailed information about the study is shown in Table 7.

[0413] [Table 7]

[0414] pain measurement

[0415] The rats were subjected to mechanical allodynia testing 1 hour before and 1 hour after administration of the test substance according to the method described in Example 1 on days 7 (D7) and 14 (D14), respectively.

[0416] result

[0417] Figure 4 shows the 50% PWT values ​​of rats from the sham group, model group, and treatment group (SEQ ID NO: 29, intravenous, continuous administration) obtained from the mechanical allodynia test in Example 6. Before administration on day 7 (D7), the pain threshold of rats in the model group was significantly reduced compared to the sham group, and there was no significant difference between the pain threshold of rats in the treatment group and the pain threshold of rats in the model group; one hour after administration on day 7 (D7), the pain threshold of rats in the treatment group was significantly increased compared to the model group; before administration on day 14 (D14), the pain threshold of rats in the treatment group was significantly increased compared to the model group; one hour after administration on day 14 (D14), the pain threshold of rats in the treatment group was significantly increased compared to the model group. In summary, the data in Figure 4 suggest that the pain threshold of rats in the model group was significantly reduced compared to the sham group, indicating successful modeling. Furthermore, it was also shown that compared with the model group, the pain threshold of rats in the treatment group gradually increased with increasing number of doses, indicating a significant analgesic effect.

[0418] Example 7: Effect of polypeptides of the present disclosure administered via intraperitoneal route on the treatment of cancer pain associated with cisplatin-induced chemotherapy-induced peripheral neuropathy model in mice The administration of chemotherapy agents can cause damage to peripheral nerves, resulting in chemotherapy-induced peripheral neuropathy (CIPN). Cancer pain associated with CIPN is one of the typical symptoms of CIPN. This pain can be described as a burning, tingling, or prickling sensation, and patients have difficulty controlling fine motor skills. This pain is very common in cancer patients undergoing chemotherapy, especially those treated with cytotoxic agents (e.g., platinum anticancer drugs, vinca alkaloids, taxanes, proteasomes, and angiogenesis inhibitors). Therefore, in this example, the effect of an exemplary polypeptide of the present disclosure, i.e., SEQ ID NO: 29, administered via intraperitoneal (ip) route on pain treatment was investigated in a cancer pain model associated with chemotherapy-induced peripheral neuropathy induced by cisplatin in mice.

[0419] General Experimental Protocol

[0420] The experiment in this example was divided into two parts. In the first part (Part I), SEQ ID NO: 29 was administered in parallel with modeling to investigate the preventive effect of the polypeptide of the present disclosure on cancer pain associated with CIPN, particularly cisplatin-induced CIPN. In the second part (Part II), mechanical allodynia tests were performed on mice to confirm that the animals still had CIPN-associated cancer pain after SEQ ID NO: 29 was eluted from the mouse body, and to investigate the therapeutic effect of the polypeptide of the present disclosure on CIPN-associated cancer pain after modeling.

[0421] Grouping and administration

[0422] Forty-four male C57BL / 6 mice weighing 20-25 g were randomly divided into four groups: 8 mice in the control group (Group 1, administered vehicle (saline)), 12 mice in the model group (Group 2, administered vehicle (saline) and cisplatin (2.3 mg / kg, intraperitoneally, once daily)), 12 mice in the treatment group (once daily) (Group 3, administered SEQ ID NO: 29 (15 mg / kg, intraperitoneally, once daily) and cisplatin (2.3 mg / kg, intraperitoneally, once daily)), and 12 mice in the treatment group (twice daily) (Group 4, administered SEQ ID NO: 29 (15 mg / kg, intraperitoneally, twice daily) and cisplatin (2.3 mg / kg, intraperitoneally, once daily)).

[0423] SEQ ID NO: 29 was administered on the scheduled days. Briefly, SEQ ID NO: 29 was administered by intraperitoneal injection once or twice daily on days 1 through 11, followed by a washout period spanning days 12 through 23. SEQ ID NO: 29 administration then resumed according to the same regimen as above and continued from days 24 through 30.

[0424] More detailed information about the studies is provided in Table 8.

[0425] [Table 8-1] [Table 8-2]

[0426] pain measurement

[0427] Mice were subjected to mechanical allodynia testing at 0 hours before and 2 hours after the first administration of the test substance (saline or SEQ ID NO: 29) according to the method described in Example 1 on days 6, 10, 23 and 30, respectively.

[0428] result

[0429] Figure 5 shows the 50% PWT values ​​of mice from the control group, model group, treatment group (once a day) (SEQ ID NO: 29, intraperitoneally, once a day), and treatment group (twice a day) (SEQ ID NO: 29, intraperitoneally, twice a day) obtained from the mechanical allodynia test in Example 7. Figure 5 confirms that the polypeptide of the present disclosure has a preventive effect on cancer pain associated with CIPN. Specifically, the results of pain measurements on days 6 and 10 showed that the pain thresholds of mice from the treatment group (close to the pain thresholds of mice from the control group) were significantly higher than the pain thresholds of mice from the model group. It was also found that the pain threshold levels of mice differed (i.e., were dose-related) at different administration frequencies. Figure 5 also confirms that the polypeptide of the present disclosure has a therapeutic effect on cancer pain associated with CIPN. In particular, the results of pain measurements on day 30 showed that the pain threshold of mice from the treatment group significantly increased after 7 days of continuous administration of sequence number 29 (see changes in pain threshold of mice from the treatment group on day 30 vs. day 23).

[0430] Example 8: Effect of polypeptides of the present disclosure administered via the ocular route on the treatment of benzalkonium chloride-induced eye pain model in mice Ocular pain, also known as ocular pain, can be described as a sharp, aching, or throbbing pain in one or both eyes. Ocular pain can be broadly classified as ocular nociceptive pain and ocular neuropathic pain. Ocular nociceptive pain is often caused by various injuries to the front of the eye, such as injuries, surgery, contact lenses, and foreign bodies. In contrast, ocular neuropathic pain refers to the heightened perception of ocular pain in response to normally non-painful stimuli. This condition can result from repeated direct damage to the corneal nerve, where abnormal regeneration of the corneal nerve and upregulation of nociceptors involved in processing painful stimuli result in increased pain perception even in response to normally non-painful stimuli. In this example, the effect of an exemplary polypeptide of the present disclosure, i.e., SEQ ID NO: 29, administered via the ocular route (as eye drops) on pain treatment was examined in a benzalkonium chloride-induced ocular pain (ocular neuropathic pain) model in mice.

[0431] Modeling

[0432] C57BL / 6JNifdc mice were used in the experiment. Briefly, each mouse was fixed with one hand, and one eye was held open with the other hand (and fixed by another laboratory assistant). The model drug, i.e., 0.1% benzalkonium chloride, was instilled into one eye (twice a day (9:00, 17:00), 10 μL each time) and held for 30 seconds. This procedure was repeated for 6 days.

[0433] To evaluate the pathological changes in the front of the mouse's eyeball, slit lamp photographs were taken on the third day after the start of modeling. According to the photographic results, the mouse's eyes were scored from three angles, including corneal opacity (0: clear, 1: visible opacity, 2: difficult to find, 3: pupil not visible), conjunctival edema (0: absent, 1: mild edema, 2: edema, 3: severe edema), and congestion (0: absent, 1: mild congestion, 2: congestion, 3: severe congestion, 4: bleeding), to access and evaluate the damage in the front of the mouse's eyeball. Then, the mice were randomly assigned to groups.

[0434] Grouping and administration

[0435] Based on the scores in the anterior eye evaluation, 18 model mice were randomly divided into two groups: 9 mice in the model group and 9 mice in the test substance group, while another 9 mice that did not undergo modeling constituted the control group.

[0436] The polypeptide of the present disclosure was administered to the test substance group according to the following regimen. Specifically, each mouse was immobilized with one hand, and the other hand was used to hold the model eye open. Using a pipette, the test substance (SEQ ID NO: 29) was instilled into the model eye (10 μL each time, 30 μg / ml concentration, three times a day (9:00, 13:00, 17:00)) and maintained for 30 seconds. This procedure was repeated for two days. Next, a scratching behavior test was performed to examine the analgesic effect of the test substance on eye pain in mice.

[0437] More detailed information on grouping and dosing is provided in Table 9.

[0438] [Table 9]

[0439] pain measurement

[0440] Scratching behavior test: The mice were administered into the eyes for two consecutive days. After the first administration on the morning of the third day, the mice were released into the test cage and allowed to adapt to the environment. After the mice had adapted for 20 minutes, 2M NaCl hypertonic saline was dropped into the eyes of the mice (7 μL / mouse). After the action for 5 seconds, the mice were released back into the cage, and the number of times they wiped their eyes within 30 seconds was counted.

[0441] result

[0442] Figure 6 shows the number of times mice from each group wiped their eyes in the scratching behavior test. During the modeling process, the cornea and conjunctiva of the mice were damaged by continuous administration of 0.1% benzalkonium chloride, causing symptoms such as eye pain and itching. Therefore, two days after treatment, a scratching behavior test was performed to observe the occurrence of eye wiping behavior with the mice's forepaws. Mice in the model group exhibited a significantly increased number of eye wiping behaviors compared to mice in the control group (P<0.05). In contrast, mice in the test substance group exhibited a significantly decreased number of eye wiping behaviors compared to mice in the model group after administration of the test substance (P<0.01). These results indicated that the test substance could significantly improve eye pain symptoms in mice.

[0443] Sequence Listing [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4]

Claims

1. An artificial polypeptide of formula (VI): X-Y (VI), wherein X is a moiety comprising a variant of the sequence of SEQ ID NO: 1, said variant being characterized in that it has at least one, two, three, four, five, six, seven, eight or nine D in SEQ ID NO: 1 mutated to S, and / or at least one, two, three, four, five or six E in SEQ ID NO: 1 mutated to T; and Y is a moiety comprising a variant of the sequence of SEQ ID NO: 2, said variant being characterized in that it has at least one, two, three, four or five C's in SEQ ID NO: 2 mutated to A's).

2. 10. The artificial polypeptide of claim 1, wherein X comprises a sequence having at least 70% identity to SEQ ID NO:1, and / or X comprises a sequence having at most 95% identity to SEQ ID NO:

1.

3. 3. The artificial polypeptide of claim 1 or 2, wherein Y comprises a sequence having at least 80% identity to SEQ ID NO:2, and / or Y comprises a sequence having at most 95% identity to SEQ ID NO:

2.

4. 4. The artificial polypeptide of any one of claims 1-3, wherein at least 50% of the amino acids of Y are selected from I, V, L, F, C, M, and A.

5. 5. The artificial polypeptide of any one of claims 1-4, wherein the total number of R, K, T, A, N, Q, D, E, S, and G in X is greater than 30, and / or the total number of W, Y, F, M, L, I, and V in X is 20 or less.

6. 6. The artificial polypeptide of any one of claims 1-5, wherein the total number of R, K, T, A, N, Q, D, E, S, and G in Y is greater than 10, and / or the total number of W, Y, F, M, L, I, and V in Y is 20 or less.

7. 7. The artificial polypeptide of any one of claims 1-6, wherein X comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs:80-83, or X comprises a sequence that is any one selected from SEQ ID NOs:80-83, or X is a sequence that is any one selected from SEQ ID NOs:80-83.

8. 8. The artificial polypeptide of any one of claims 1-7, wherein Y comprises a sequence having at least 80% identity to SEQ ID NO:3, or Y comprises the sequence of SEQ ID NO:3, or Y is the sequence of SEQ ID NO:

3.

9. 9. The artificial polypeptide of any one of claims 1-8, wherein the artificial polypeptide comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs:90-93, or the artificial polypeptide comprises a sequence that is any one selected from SEQ ID NOs:90-93, or the artificial polypeptide is a sequence that is any one selected from SEQ ID NOs:90-93.

10. An artificial polypeptide of formula (VII): X-Y (VII), wherein X is a moiety comprising a variant of the sequence of SEQ ID NO: 1, said variant being characterized by having at least 1, 2, 3, 4 or 5 amino acid insertions compared to SEQ ID NO: 1; and Y is a moiety comprising 10 to 30 amino acids, and Y comprises a sequence having at least 15 consecutive AA of SEQ ID NO:2).

11. 11. The artificial polypeptide of claim 10, wherein the amino acid insertion is located N-terminal to X and / or the inserted amino acid is M.

12. 12. The artificial polypeptide of claim 10 or 11, wherein Y, is a moiety comprising a variant of the sequence of SEQ ID NO:2, wherein the variant has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids truncated compared to SEQ ID NO:2, and optionally the at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids truncated at the C-terminus of Y,.

13. 13. The artificial polypeptide of any one of claims 10-12, wherein at least 50% of the amino acids in X are selected from R, K, N, D, Q, E, and H, and / or at most 60% of the amino acids in X are selected from R, K, N, D, Q, E, and H.

14. 14. The artificial polypeptide of any one of claims 10-13, wherein the total number of E or D in X is at least 8 and / or the total number of E or D in X is at most 15.

15. 15. The artificial polypeptide of any one of claims 10-14, wherein the total number of R, K, T, A, N, Q, D, E, S, and G in X is greater than 30, and / or the total number of W, Y, F, M, L, I, and V in X is 20 or less.

16. 16. The artificial polypeptide of any one of claims 10-15, wherein Y, comprises 15-25 amino acids, or Y, comprises 18-25 amino acids, or Y, comprises 20-25 amino acids.

17. 17. The artificial polypeptide of any one of claims 10-16, wherein 40-65% of the amino acids of Y are selected from I, V, L, F, C, M, and A.

18. 18. The artificial polypeptide of any one of claims 10-17, wherein the total number of R, K, T, A, N, Q, D, E, S, and G in Y is 10 or less, and / or the total number of W, Y, F, M, L, I, and V in Y is 15 or less.

19. 19. The artificial polypeptide of any one of claims 10-18, wherein X comprises a sequence having at least 80% identity to SEQ ID NO:96, or X comprises the sequence of SEQ ID NO:96, or X is the sequence of SEQ ID NO:

96.

20. 20. The artificial polypeptide of any one of claims 10-19, wherein Y, comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs:97-103, or Y comprises a sequence that is any one selected from SEQ ID NOs:97-103, or Y is a sequence that is any one selected from SEQ ID NOs:97-103.

21. 21. The artificial polypeptide of any one of claims 10-20, wherein the artificial polypeptide comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 104-110, or the artificial polypeptide comprises a sequence that is any one selected from SEQ ID NOs: 104-110, or the artificial polypeptide is a sequence that is any one selected from SEQ ID NOs: 104-110.

22. Artificial polypeptides of formula (I) X-Y(I), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1; Y is a moiety comprising 10 to 50 amino acids, at least 50% of which are selected from I, V, L, F, C, M and A; Y contains a total number of cysteines (C) of less than 5. wherein the mutant has at least 1, 2, 3, 4, 5, 6, 7, 8 or 9 D in X mutated to S, and / or at least 1, 2, 3, 4, 5 or 6 E in X mutated to T.

23. 23. The variant of claim 22, wherein at least 20% of the amino acids in X are selected from R, K, N, D, Q, E and H, at least 30% of the amino acids in X are selected from R, K, N, D, Q, E and H, at most 90% of the amino acids in X are selected from R, K, N, D, Q, E and H, and / or at most 80% of the amino acids in X are selected from R, K, N, D, Q, E and H.

24. 24. The variant of claim 22 or 23, wherein X comprises a sequence having at least 70% identity to SEQ ID NO:

1.

25. 25. The variant of any one of claims 22 to 24, wherein Y comprises a total number of cysteines (C) of less than 4, or wherein Y comprises a total number of cysteines (C) of less than 3.

26. 26. The variant of any one of claims 22-25, wherein the total number of hydrophobic amino acids in Y, is greater than 8, or said total number of hydrophobic amino acids in Y, is greater than 12, or said total number of hydrophobic amino acids in Y, is greater than 15, and / or the total number of hydrophilic amino acids in Y, is 5 or less.

27. 27. The variant of any one of claims 22 to 26, wherein Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-15, 58-61 and 84-85, or wherein Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-18, 58-61 and 84-85.

28. An artificial polypeptide of formula (II) X-Y(II), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1; Y is a moiety comprising 10 to 50 amino acids, at least 50% of which are selected from I, V, L, F, C, M and A; Y comprises a sequence having at most 90% identity to SEQ ID NO:2 wherein the mutant has at least 1, 2, 3, 4, 5, 6, 7, 8 or 9 D in X mutated to S, and / or at least 1, 2, 3, 4, 5 or 6 E in X mutated to T.

29. 29. The variant of claim 28, wherein at least 20% of the amino acids in X are selected from R, K, N, D, Q, E and H, at least 30% of the amino acids in X are selected from R, K, N, D, Q, E and H, at most 90% of the amino acids in X are selected from R, K, N, D, Q, E and H, and / or at most 80% of the amino acids in X are selected from R, K, N, D, Q, E and H.

30. 30. The variant of claim 28 or 29, wherein X comprises a sequence having at least 70% identity to SEQ ID NO:

1.

31. 31. The variant of any one of claims 28 to 30, wherein Y comprises a sequence having at most 80% identity to SEQ ID NO:2, or wherein Y comprises a sequence having at most 70% identity to SEQ ID NO:

2.

32. 32. The variant of any one of claims 28-31, wherein the total number of hydrophobic amino acids in Y, is greater than 8, or said total number of hydrophobic amino acids in Y, is greater than 12, or said total number of hydrophobic amino acids in Y, is greater than 15, and / or the total number of hydrophilic amino acids in Y, is 5 or less.

33. 33. The variant of any one of claims 28 to 32, wherein Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 16 to 18, or wherein Y comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 16 to 18.

34. An artificial polypeptide of formula (III) X-Y (III), wherein X is a moiety comprising 40 to 65 amino acids, at least 50% of which are selected from H, R, K, D, Q, N and E; Y is a moiety comprising a sequence having at least 80% identity with SEQ ID NO: 2; The total number of H, R, K, D, Q, N, and E in X is less than 33. wherein the mutant has at least 1, 2, 3, 4, 5, 6, 7, 8 or 9 D in X mutated to S, and / or at least 1, 2, 3, 4, 5 or 6 E in X mutated to T.

35. 35. The variant of claim 34, wherein at least 20% of the amino acids in X are selected from R, K, N, D, Q, E and H, at least 30% of the amino acids in X are selected from R, K, N, D, Q, E and H, at most 90% of the amino acids in X are selected from R, K, N, D, Q, E and H, and / or at most 80% of the amino acids in X are selected from R, K, N, D, Q, E and H.

36. 36. The variant of claim 34 or 35, wherein X comprises a sequence having at least 70% identity to SEQ ID NO:

1.

37. 37. The variant of any one of claims 34 to 36, wherein Y comprises a sequence having at least 90% identity to SEQ ID NO:2, or wherein Y comprises the sequence of SEQ ID NO:

2.

38. 38. The variant of any one of claims 34 to 37, wherein at least 50% of the amino acids of Y are selected from I, V, L, F, C, M and A.

39. 39. The variant of any one of claims 34 to 38, wherein the total number of H, R, K, D, Q, N and E in X is less than 30, or the total number of H, R, K, D, Q, N and E in X is less than 25, or the total number of H, R, K, D, Q, N and E in X is less than 20.

40. 40. The variant of any one of claims 34 to 39, wherein the total number of hydrophilic amino acids in X is greater than 10, the total number of hydrophilic amino acids in X is greater than 15, the total number of hydrophilic amino acids in X is greater than 20, the total number of hydrophilic amino acids in X is greater than 25, the total number of hydrophobic amino acids in X is 15 or less, and / or the total number of hydrophobic amino acids in X is 10 or less.

41. An artificial polypeptide of formula (IV) X-Y(IV), wherein X is a moiety comprising 40 to 65 amino acids, at least 50% of which are selected from H, R, K, D, Q, N and E; Y is a moiety comprising a sequence having at least 80% identity with SEQ ID NO: 2; X comprises a sequence having at most 90% identity with SEQ ID NO:

1. wherein the mutant has at least 1, 2, 3, 4, 5, 6, 7, 8 or 9 D in X mutated to S, and / or at least 1, 2, 3, 4, 5 or 6 E in X mutated to T.

42. 42. The variant of claim 41 , wherein at least 20% of the amino acids in X are selected from R, K, N, D, Q, E and H, at least 30% of the amino acids in X are selected from R, K, N, D, Q, E and H, at most 90% of the amino acids in X are selected from R, K, N, D, Q, E and H, and / or at most 80% of the amino acids in X are selected from R, K, N, D, Q, E and H.

43. 43. The variant of claim 41 or 42, wherein X comprises a sequence having at least 70% identity to SEQ ID NO:

1.

44. 44. The variant of any one of claims 41 to 43, wherein Y comprises a sequence having at least 90% identity to SEQ ID NO:2, or wherein Y comprises the sequence of SEQ ID NO:

2.

45. 45. The variant of any one of claims 41 to 44, wherein at least 50% of the amino acids of Y are selected from I, V, L, F, C, M and A.

46. 46. ​​The variant of any one of claims 41 to 45, wherein the total number of hydrophilic amino acids in X is greater than 10, the total number of hydrophilic amino acids in X is greater than 15, the total number of hydrophilic amino acids in X is greater than 20, the total number of hydrophilic amino acids in X is greater than 25, the total number of hydrophobic amino acids in X is 15 or less, and / or the total number of hydrophobic amino acids in X is 10 or less.

47. An artificial polypeptide of formula (V) X-Y(V), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1; Y is a moiety comprising 10 to 30 amino acids, and Y comprises a sequence having at least 10 consecutive AA of SEQ ID NO:

2. wherein the mutant has at least 1, 2, 3, 4, 5, 6, 7, 8 or 9 D in X mutated to S, and / or at least 1, 2, 3, 4, 5 or 6 E in X mutated to T.

48. 48. The variant of claim 47, wherein at least 20% of the amino acids in X are selected from R, K, N, D, Q, E and H, at least 30% of the amino acids in X are selected from R, K, N, D, Q, E and H, at most 90% of the amino acids in X are selected from R, K, N, D, Q, E and H, and / or at most 80% of the amino acids in X are selected from R, K, N, D, Q, E and H.

49. 49. The variant of claim 47 or 48, wherein Y, comprises from 10 to 25 amino acids, or Y, comprises from 10 to 20 amino acids, or Y, comprises from 10 to 15 amino acids.

50. 50. The variant of any one of claims 47 to 49, wherein X comprises a sequence having at least 70% identity to SEQ ID NO:

1.

51. 51. The variant of any one of claims 47 to 50, wherein Y comprises a sequence which has at most 80% identity to SEQ ID NO:2, or wherein Y comprises a sequence which has at most 70% identity to SEQ ID NO:2, or wherein Y comprises a sequence which has at most 50% identity to SEQ ID NO:

2.

52. A formulation comprising an artificial polypeptide according to any one of claims 1 to 21 or a variant according to any one of claims 22 to 51, and a pharmaceutically acceptable excipient.

53. 1. A method for treating or preventing pain in a subject in need thereof, comprising: an effective amount of an artificial polypeptide of formula (I): X-Y(I), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1; and Y is a moiety comprising 10 to 50 amino acids, at least 50% of which are selected from I, V, L, F, C, M and A; Y contains a total number of cysteines (C) of less than 5. to said subject.

54. 54. The method of claim 53, wherein X comprises a sequence having at least 90% identity to SEQ ID NO:1, or wherein X comprises a sequence having at least 95% identity to SEQ ID NO:1, or wherein X comprises the sequence of SEQ ID NO:

1.

55. 55. The method of claim 53 or 54, wherein at least 50% of the amino acids in X are selected from R, K, N, D, Q, E and H.

56. 56. The method of any one of claims 53 to 55, wherein Y comprises a total number of cysteines (C) of less than 4, or wherein Y comprises a total number of cysteines (C) of less than 3, or wherein Y comprises a total number of cysteines (C) of less than 2.

57. 57. The method of any one of claims 53 to 56, wherein the total number of hydrophobic amino acids in Y, is greater than 8, said total number of hydrophobic amino acids in Y, is greater than 12, said total number of hydrophobic amino acids in Y, is greater than 15, and / or the total number of hydrophilic amino acids in Y, is 5 or less.

58. 58. The method of any one of claims 53 to 57, wherein X comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 81 to 83.

59. 59. The method of any one of claims 53 to 58, wherein Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-15, 58-61 and 84-85, or wherein Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 3-18, 58-61 and 84-85.

60. 60. The method of any one of claims 53 to 59, wherein the polypeptide comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 29-41, 54-57, 75 and 91-95.

61. 1. A method for treating or preventing pain in a subject in need thereof, comprising: an effective amount of an artificial polypeptide of formula (II): X-Y(II), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1; and Y is a moiety comprising 10 to 50 amino acids, at least 50% of which are selected from I, V, L, F, C, M and A; Y comprises a sequence having at most 90% identity to SEQ ID NO:2 to said subject.

62. 62. The method of claim 61 , wherein X comprises a sequence having at least 90% identity to SEQ ID NO:1, or wherein X comprises a sequence having at least 95% identity to SEQ ID NO:1, or wherein X comprises the sequence of SEQ ID NO:

1.

63. 63. The method of claim 61 or 62, wherein at least 50% of the amino acids in X are selected from R, K, N, D, Q, E and H.

64. 64. The method of any one of claims 61 to 63, wherein Y comprises a sequence that has at most 80% identity to SEQ ID NO:2, or wherein Y comprises a sequence that has at most 70% identity to SEQ ID NO:2, or wherein Y comprises a sequence that has at most 50% identity to SEQ ID NO:

2.

65. 65. The method of any one of claims 61 to 64, wherein the total number of hydrophobic amino acids in Y, is greater than 8, said total number of hydrophobic amino acids in Y, is greater than 12, said total number of hydrophobic amino acids in Y, is greater than 15, and / or the total number of hydrophilic amino acids in Y, is 5 or less.

66. 66. The method of any one of claims 61 to 65, wherein Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 16 to 18, or wherein Y comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 16 to 18.

67. 67. The method of any one of claims 61 to 66, wherein the polypeptide comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 42 to 44.

68. 1. A method for treating or preventing pain in a subject in need thereof, comprising: an effective amount of an artificial polypeptide of formula (III): X-Y (III), wherein X is a moiety comprising 40 to 65 amino acids, at least 50% of which are selected from H, R, K, D, Q, N and E; and Y is a moiety comprising a sequence having at least 80% identity with SEQ ID NO: 2; The total number of H, R, K, D, Q, N, and E in X is less than 33. to said subject.

69. 69. The method of claim 68, wherein Y comprises a sequence having at least 90% identity to SEQ ID NO:2, or Y comprises a sequence having at least 95% identity to SEQ ID NO:2, or Y comprises the sequence of SEQ ID NO:

2.

70. 70. The method of claim 68 or 69, wherein at least 50% of the amino acids of Y are selected from I, V, L, F, C, M and A.

71. 71. The method of any one of claims 68 to 70, wherein the total number of H, R, K, D, Q, N and E in X is less than 30, or the total number of H, R, K, D, Q, N and E in X is less than 25, or the total number of H, R, K, D, Q, N and E in X is less than 20.

72. 72. The method of any one of claims 68-71, wherein the total number of hydrophilic amino acids in X is greater than 10, the total number of hydrophilic amino acids in X is greater than 15, the total number of hydrophilic amino acids in X is greater than 20, the total number of hydrophilic amino acids in X is greater than 25, the total number of hydrophobic amino acids in X is 15 or less, and / or the total number of hydrophobic amino acids in X is 10 or less.

73. 73. The method of any one of claims 68 to 72, wherein X comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 23 to 27, or wherein X comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 23 to 27.

74. 74. The method of any one of claims 68 to 73, wherein the polypeptide comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 49 to 53.

75. 1. A method for treating or preventing pain in a subject in need thereof, comprising: an effective amount of an artificial polypeptide of formula (IV): X-Y(IV), wherein X is a moiety comprising 40 to 65 amino acids, at least 50% of which are selected from H, R, K, D, Q, N and E; and Y is a moiety comprising a sequence having at least 80% identity with SEQ ID NO: 2; X comprises a sequence having at most 90% identity with SEQ ID NO:

1. to said subject.

76. 76. The method of claim 75, wherein X comprises a sequence having at most 80% identity to SEQ ID NO:1, or wherein X comprises a sequence having at most 70% identity to SEQ ID NO:1, or wherein X comprises a sequence having at most 50% identity to SEQ ID NO:

1.

77. 77. The method of claim 75 or 76, wherein Y comprises a sequence having at least 90% identity to SEQ ID NO:2, or Y comprises a sequence having at least 95% identity to SEQ ID NO:2, or Y comprises the sequence of SEQ ID NO:

2.

78. 78. The method of any one of claims 75 to 77, wherein at least 50% of the amino acids of Y are selected from I, V, L, F, C, M and A.

79. 79. The method of any one of claims 75 to 78, wherein the total number of hydrophilic amino acids in X is greater than 10, the total number of hydrophilic amino acids in X is greater than 15, the total number of hydrophilic amino acids in X is greater than 20, the total number of hydrophilic amino acids in X is greater than 25, the total number of hydrophobic amino acids in X is 15 or less, and / or the total number of hydrophobic amino acids in X is 10 or less.

80. 80. The method of any one of claims 75 to 79, wherein X comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 19-22 and 76-79, or wherein X comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 19-22 and 76-79.

81. 81. The method of any one of claims 75 to 80, wherein the polypeptide comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 45-48 and 86-89.

82. 1. A method for treating or preventing pain in a subject in need thereof, comprising: an effective amount of an artificial polypeptide of formula (V): X-Y(V), wherein X is a moiety comprising a sequence having at least 80% identity to SEQ ID NO: 1; and Y is a moiety comprising 10 to 30 amino acids, Y comprises a sequence having at least 10 consecutive AA of SEQ ID NO:

2. to said subject.

83. 83. The method of claim 82, wherein Y, comprises from 10 to 25 amino acids, or Y, comprises from 10 to 20 amino acids, or Y, comprises from 10 to 15 amino acids.

84. 84. The method of claim 82 or 83, wherein X comprises a sequence having at least 90% identity to SEQ ID NO:1, or wherein X comprises a sequence having at least 95% identity to SEQ ID NO:1, or wherein X comprises the sequence of SEQ ID NO:

1.

85. 85. The method of any one of claims 82 to 84, wherein at least 50% of the amino acids in X are selected from R, K, N, D, Q, E and H.

86. 86. The method of any one of claims 82 to 85, wherein X comprises a sequence having at least 80% identity to SEQ ID NO:96, or X comprises a sequence having at least 90% identity to SEQ ID NO:96, or X comprises a sequence having at least 95% identity to SEQ ID NO:96, or X comprises the sequence of SEQ ID NO:

96.

87. 87. The method of any one of claims 82 to 86, wherein Y comprises a sequence which has at most 80% identity to SEQ ID NO:2, or wherein Y comprises a sequence which has at most 70% identity to SEQ ID NO:2, or wherein Y comprises a sequence which has at most 50% identity to SEQ ID NO:

2.

88. 88. The method of any one of claims 82-87, wherein Y comprises a sequence having at least 80% identity to any one selected from SEQ ID NOs: 97-103, or Y comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 97-103, or Y comprises a sequence having at least 95% identity to any one selected from SEQ ID NOs: 97-103, or Y comprises a sequence which is any one selected from SEQ ID NOs: 97-103.

89. 89. The method of any one of claims 82 to 88, wherein the polypeptide comprises a sequence having at least 90% identity to any one selected from SEQ ID NOs: 53-56 and 104-110.

90. 100. A method for treating or preventing pain in a subject in need thereof, comprising administering to the subject an effective amount of the artificial polypeptide of any one of claims 1-21 or the variant of any one of claims 22-51.

91. The method according to any one of claims 53 to 90, wherein the pain is at least one selected from the group consisting of acute pain, chronic pain, and transitional pain.

92. 92. The method of claim 91, wherein the acute pain is at least one selected from the group consisting of pain associated with acute injury, acute inflammatory pain, and headache.

93. 93. The method of claim 92, wherein the pain associated with an acute injury is acute post-operative pain.

94. 92. The method of claim 91, wherein the chronic pain is at least one selected from the group consisting of nociceptive pain, neuropathic pain, and mixed pain.

95. 95. The method of claim 94, wherein the nociceptive pain is at least one selected from the group consisting of abdominal pain, anal fissure pain, bladder pain, complex regional pain syndrome, breast pain, intestinal spasm, bladder pain syndrome, joint pain, musculoskeletal pain, muscle pain, myofascial pain syndrome, nociceptive bone pain, pain associated with pancreatitis, polymyalgia rheumatica, chronic post-operative pain, renal pain, somatic pain, tendon pain, ligament pain, chronic traumatic pain, pain associated with fractures, and visceral pain.

96. 96. The method of claim 95, wherein the breast pain is cyclical breast pain.

97. 96. The method of claim 95, wherein the renal pain is renal colic.

98. 96. The method of claim 95, wherein the pain associated with a fracture is pain associated with a spinal fracture.

99. 95. The method of claim 94, wherein the mixed pain is at least one selected from the group consisting of arthritis pain, back pain, cancer pain, dental pain, fibromyalgia, chronic inflammatory pain, lower back pain, neck pain, and eye pain.

100. 100. The method of claim 99, wherein the arthritis pain is at least one selected from the group consisting of osteoarthritis pain, rheumatoid arthritis pain, and gout pain.

101. 100. The method of claim 99, wherein the cancer pain is tumor-associated cancer pain.

102. 102. The method of claim 101, wherein the cancer pain associated with a tumor is at least one selected from the group consisting of cancer-related nerve pain, cancer-related bone pain, cancer-related soft tissue pain, and cancer-related referred pain.

103. 103. The method of claim 102, wherein the bone pain associated with cancer is at least one selected from the group consisting of bone pain associated with bone cancer and bone metastatic tumors.

104. 104. The method of claim 103, wherein the bone pain associated with bone cancer is at least one selected from the group consisting of bone pain associated with chondrosarcoma, bone pain associated with Ewing's sarcoma, bone pain associated with malignant fibrous histiocytoma of bone, bone pain associated with osteosarcoma, and bone pain associated with fibrochondromeschymoma of bone.

105. 100. The method of claim 99, wherein the cancer pain is cancer pain associated with a diagnostic and / or therapeutic procedure.

106. 106. The method of claim 105, wherein the cancer pain associated with a diagnostic and / or therapeutic procedure is cancer-associated phantom pain.

107. 106. The method of claim 105, wherein the cancer pain associated with a diagnostic and / or therapeutic procedure is chemotherapy-associated cancer pain.

108. 108. The method of claim 107, wherein the cancer pain associated with chemotherapy is cancer pain associated with chemotherapy-induced peripheral neuropathy.

109. 109. The method of claim 107 or 108, wherein the chemotherapy is carried out by administration of a cytotoxic agent to a subject in need thereof.

110. The method of claim 109, wherein the cytotoxic agent is at least one selected from the group consisting of platinum anticancer agents (e.g., cisplatin, carboplatin, nedaplatin, and oxaliplatin), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), taxanes (e.g., paclitaxel and docetaxel), and proteasome or angiogenesis inhibitors (e.g., bortezomib, carfilzomib, and thalidomide).

111. 100. The method of claim 99, wherein the ocular pain is at least one selected from the group consisting of ocular nociceptive pain and ocular neuropathic pain.

112. 112. The method of claim 111, wherein the ocular nociceptive pain is at least one selected from the group consisting of ocular pain associated with injury, ocular pain associated with surgery, ocular pain associated with contact lens wear, and ocular pain associated with the irritation of a foreign body.

113. 112. The method of claim 111, wherein the ocular neuropathic pain is at least one selected from the group consisting of ocular pain associated with allergies, ocular pain associated with infections, ocular pain associated with inflammation, ocular pain associated with chronic ocular surface disease, postoperative ocular neuropathic pain, ocular pain associated with toxic keratopathy, ocular pain associated with radiation, ocular pain associated with ultraviolet light exposure, ocular pain associated with systemic neuropathy, traumatic ocular neuropathic pain, ocular pain associated with trigeminal neuralgia, and ocular pain associated with fibromyalgia.

114. 112. The method of claim 111, wherein the ocular neuropathic pain is at least one selected from the group consisting of corneal neuralgia, conjunctival neuralgia, optic nerve neuralgia, extraocular muscle neuralgia, orbital neuralgia, and palpebral neuralgia.

115. 95. The method of claim 94, wherein the neuropathic pain is at least one selected from the group consisting of central neuropathic pain and peripheral neuropathic pain.

116. 116. The method of claim 115, wherein the central neuropathic pain is at least one selected from the group consisting of post-stroke neuropathic pain, syringomyelia pain, neuropathic pain associated with ischemic myelopathy, neuropathic pain associated with compressive myelopathy, neuropathic pain associated with radiation myelopathy, neuropathic pain associated with spinal cord injury, neuropathic pain associated with multiple sclerosis, neuropathic pain associated with Parkinson's disease, phantom limb pain, and neuropathic pain associated with myelitis.

117. The method of claim 115, wherein the peripheral neuropathic pain is at least one selected from the group consisting of peripheral neuropathic pain associated with metabolic disorders or ischemia, peripheral neuropathic pain associated with infection, peripheral neuropathic pain associated with nerve or nerve root compression, peripheral neuropathic pain associated with chemotherapy, peripheral neuropathic pain associated with radiation therapy, peripheral neuropathic pain associated with stump pain, peripheral neuropathic pain associated with neuropathy due to tumor compression or infiltration, peripheral neuropathic pain associated with alcoholic polyneuropathy, peripheral neuropathic pain associated with nutritional neuropathy, peripheral neuropathic pain associated with toxic peripheral neuropathy, and peripheral neuropathic pain associated with immune neuropathy.

118. 118. The method of claim 117, wherein the peripheral neuropathic pain associated with a metabolic disorder or ischemia is at least one selected from the group consisting of diabetic peripheral neuropathic pain and ischemic peripheral neuropathic pain.

119. 118. The method of claim 117, wherein the peripheral neuropathic pain associated with an infection is at least one selected from the group consisting of peripheral neuropathic pain associated with a viral infection and peripheral neuropathic pain associated with a spirochete infection.

120. 120. The method of claim 119, wherein the peripheral neuropathic pain associated with a viral infection is at least one selected from the group consisting of postherpetic neuralgia and peripheral neuropathic pain associated with HIV infection.

121. 120. The method of claim 119, wherein the peripheral neuropathic pain associated with a spirochete infection is peripheral neuropathic pain associated with a syphilis infection.

122. 118. The method of claim 117, wherein the peripheral neuropathic pain associated with compression of a nerve or nerve root is at least one selected from the group consisting of sciatica, trigeminal neuralgia, glossopharyngeal neuralgia, neuropathic pain associated with radiculoneuropathy, and neuropathic pain associated with entrapment neuropathy.

123. 1. A method for treating or preventing peripheral neuropathic pain in a subject in need thereof, comprising administering to the subject an effective amount of a polypeptide having at least 70% identity to any one selected from SEQ ID NO: 28, SEQ ID NOs: 57, and 62-74, or a fragment or variant thereof.

124. 124. The method of claim 123, wherein the polypeptide is the polypeptide of any one of SEQ ID NOs: 28, 57, and 62-74, or a fragment or variant thereof; the polypeptide is the polypeptide of any one of SEQ ID NOs: 28, 57, and 62-74; the polypeptide is the polypeptide of any one of SEQ ID NOs: 28, and 62-74; or the polypeptide is the polypeptide of SEQ ID NO:

28.

125. The method of claim 123 or 124, wherein the peripheral neuropathic pain is at least one selected from the group consisting of peripheral neuropathic pain associated with metabolic disorders or ischemia, peripheral neuropathic pain associated with infection, peripheral neuropathic pain associated with nerve or nerve root compression, peripheral neuropathic pain associated with chemotherapy, peripheral neuropathic pain associated with radiation therapy, peripheral neuropathic pain associated with stump pain, peripheral neuropathic pain associated with neuropathy due to tumor compression or infiltration, peripheral neuropathic pain associated with alcoholic polyneuropathy, peripheral neuropathic pain associated with nutritional neuropathy, peripheral neuropathic pain associated with toxic peripheral neuropathy, and peripheral neuropathic pain associated with immune neuropathy.

126. 126. The method of claim 125, wherein the peripheral neuropathic pain associated with a metabolic disorder or ischemia is at least one selected from the group consisting of diabetic peripheral neuropathic pain and ischemic peripheral neuropathic pain.

127. 126. The method of claim 125, wherein the peripheral neuropathic pain associated with an infection is at least one selected from the group consisting of peripheral neuropathic pain associated with a viral infection and peripheral neuropathic pain associated with a spirochete infection.

128. 128. The method of claim 127, wherein the peripheral neuropathic pain associated with a viral infection is at least one selected from the group consisting of postherpetic neuralgia and peripheral neuropathic pain associated with HIV infection.

129. 128. The method of claim 127, wherein the peripheral neuropathic pain associated with a spirochete infection is peripheral neuropathic pain associated with a syphilis infection.

130. 126. The method of claim 125, wherein the peripheral neuropathic pain associated with compression of a nerve or nerve root is at least one selected from the group consisting of sciatica, trigeminal neuralgia, glossopharyngeal neuralgia, neuropathic pain associated with radiculoneuropathy, and neuropathic pain associated with entrapment neuropathy.

131. 131. The method of any one of claims 53 to 130, wherein the subject is a mammal, preferably, the subject is any one selected from the group consisting of a human, a primate, a rodent, a dog, a cat, a horse, a sheep and a pig.

132. 131. The method of any one of claims 53 to 130, wherein the subject is a pet, preferably the subject is any one selected from the group consisting of fish, frogs, salamanders, reptiles (e.g., turtles, lizards, snakes and iguanas), birds (e.g., parrots), mice, rats, guinea pigs, gerbils, hamsters, chinchillas, rabbits, ferrets, cats, dogs and pigs.

133. 133. The method of any one of claims 53 to 132, wherein the polypeptide or variant is administered in the form of a formulation comprising the polypeptide or variant and a pharmaceutically acceptable excipient.

134. The method of claim 133, wherein the formulation is in a form suitable for oral administration, preferably in the form of a tablet, capsule, pill, powder, granule, liquid, suspension or emulsion.

135. 134. The method of claim 133, wherein the formulation is in a form suitable for parenteral administration, preferably in the form of a sterile injectable solution, suspension, emulsion, gel (e.g., an injectable hydrogel) or sterile powder.

136. 134. The method of claim 133, wherein the formulation is in a form suitable for topical administration, preferably the formulation is in the form of a spray, aerosol, inhalable powder, ointment, cream, patch, suppository, paste, film or gel.

137. The method of claim 133, wherein the formulation is in the form of a sustained-release, controlled-release or delayed-release formulation, preferably in the form of a matrix tablet, a compressed tablet with mixed particles having different release rates, an osmotic pump tablet, a sustained-release or controlled-release capsule or microcapsule, a sustained-release or controlled-release implant, a sustained-release or controlled-release granule, a microparticle or microsphere, an enteric-coated capsule or tablet, a colonic placement formulation, a gel (e.g., a hydrogel), a liposomal formulation, an ion-exchange resin formulation, a floating formulation, a bioadhesive formulation, a stimulant-triggered release formulation and a pulsatile drug delivery system.

138. 134. The method of claim 133, wherein the formulation is for use in humans.

139. 134. The method of claim 133, wherein the formulation is a veterinary formulation.

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