Substitution of histidine with 2-thiohistidine in bioactive peptides

Patent metadata

Field	Value
Publication number	US-2024199687-A1
Application number	US-202218556587-A
Country	US
Kind code	A1
Filing date	Apr 22, 2022
Priority date	Apr 22, 2021
Publication date	Jun 20, 2024
Grant date	—

Abstract

Presented is a method to incorporate 2-thiohistidine (2-thioHis) into a peptide. Also provided are peptides incorporating 2-thioHis, compositions, and methods of using the peptides incorporating 2-thioHis. The methods may be methods for scavenging metals and/or radicals or reducing oxidative stress. 2-thioHis has the following structure:

First claim

1 . A method for making a modified peptide comprising:
contacting a reaction mixture comprising a solvent,

optionally, a carbodiimide, and, optionally, a base,
wherein R is an amine protecting group and R′ is an H or group formed from a carbodiimide, with:
i) an amine group of a first amino acid covalently attached to a resin, peptide covalently attached to a resin, a peptidomimetic covalently attached to a resin, or resin, or
ii) an alcohol of a first amino acid derivative attached to a resin, peptidomimetic attached to a resin, or resin, or
iii) a carbocation of a resin;

optionally, removing the amine protecting group of the amine group of

optionally, coupling a second amino acid, wherein the second amino acid is N-protected, to the unprotected amine;
optionally, cleaving the N-protecting group of the second amino acid,
optionally, repeating the coupling amino acid step and subsequent cleaving N-protecting group step; and
cleaving the modified peptide from the resin,

wherein the modified peptide is formed.

2 . The method according to claim 1 , further comprising functionalizing the N-terminus of the modified peptide on resin with a capping group and/or a linking group prior to cleavage.

3 . The method according to claim 2 , wherein the capping group is an acetyl group, a palmitoyl group, or an ascorbic acid group.

4 . The method according to claim 2 , wherein the linking group is a succinyl group, polyethylene glycol group, or a combination thereof.

5 . The method according to claim 1 , wherein the resin is a Rink resin, a Wang resin, a trityl resin, or a chlorotrityl resin.

6 . The method according to claim 1 , further comprising purifying the modified peptide.

7 . The method according to claim 1 , wherein the group formed from a carbodiimide is formed from diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), or 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU).

8 . The method according to claim 1 , wherein the amino acids are canonical amino acids, non-canonical amino acids, amino acid derivatives, or a combination thereof.

9 . A modified peptide comprising:

(SEQ ID NO:1, where His is replaced with 2-thioHis),
wherein is a R″ is H, a capping group, a linking group, a peptide group, or a linking group covalently bonded to a capping group and R′″ is —OH, —NH 2 , —OR″″, where R″″ is an alkyl group.

10 . The modified peptide according to claim 9 , wherein the peptide has the following structure:

(SEQ ID NO:1, where His is replaced with 2-thioHis).

11 . The modified peptide according to claim 9 , wherein the capping group is an acetyl group, a palmitoyl group, or an ascorbic acid group.

12 . The modified peptide according to claim 9 , wherein the linking group is a succinyl group, a polyethylene glycol group, or a combination thereof.

13 . The modified peptide according to claim 9 , wherein the peptide has the following structure:

(SEQ ID NO:1, where His is replaced with 2-thioHis).

14 . A composition comprising a modified peptide according to claim 9 and a carrier.

15 . The composition of claim 14 , wherein the composition is a cosmetic composition.

16 . The composition of claim 15 , wherein the cosmetic composition is a skin care product.

17 . A method for scavenging metals or radicals, comprising
contacting a solution or medium comprising metals or radicals with a modified peptide of according to claim 9 or a composition comprising the modified peptide, wherein the metals or radicals bind to the modified peptide.

18 . A method for decreasing oxidative stress in an individual in need of treatment comprising administering to an individual a therapeutically effective amount of a modified peptide according to claim 9 or a composition comprising the modified peptide, wherein the oxidative stress of the individual is decreased.

Assignees

• Univ Of Vermont And State Agricultural College

Inventors

• Hondal Robert J
• Jenny Kaelyn

Classifications

• A61Q19/00

  Preparations for care of the skin · CPC title

• A61K8/64

  Proteins; Peptides; Derivatives or degradation products thereof · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• C07K5/0815

  with the first amino acid being basic · CPC title

• C07K5/06086

  with the first amino acid being basic · CPC title