Substitution of histidine with 2-thiohistidine in bioactive peptides
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
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.