Stapled helical peptides and methods of synthesis

Patent metadata

Field	Value
Publication number	US-10011631-B2
Application number	US-201615363626-A
Country	US
Kind code	B2
Filing date	Nov 29, 2016
Priority date	Dec 1, 2015
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

Abstract

The present disclosure relates to the design and generation of stapled helical peptides that perturb protein-protein interactions (PPIs). The methods disclosed herein for preparing stapled peptides involve providing a peptide having a first amino acid that is functionalized with a salicylaldehyde ester side group and a second amino acid functionalized with a 1,2-hydroxyl amine side group; reacting the first and second amino acids to generate an N,O-benzylidene acetal moiety; and performing acidolysis of the resultant N,O-benzylidene acetal moiety to generate the stapled peptide. In many forms, the stapled helical peptides described herein are not hydrophobic.

First claim

We claim:

1. A stapled peptide, wherein the stapled peptide comprises a peptide backbone and at least one staple, wherein the stapled peptide is defined according to Formula (I) or Formula (II):

wherein:
[Xaa] is any natural or synthetic amino acid;
x is an integer from 2 to 10;
y is an integer from 2 to 10; and
z is an integer from 2 to 10,

wherein:
the staple is defined according to Formula (a) or Formula (b):

wherein:
R is H or a C 1 -C 30 alkyl group;
X is —(CH 2 ) a — or —C(O)NH—, wherein a is an integer from 1 to 6;
m is an integer from 0 to 6; and
n is an integer from 0 to 6.

2. The stapled peptide of claim 1 , wherein the staple is hydrophilic.

3. The stapled peptide of claim 1 , wherein for the staple according to Formula (a) R is H.

4. The stapled peptide of claim 1 , wherein for the staple according to Formula (a) X is —(CH 2 ) a —.

5. The stapled peptide of claim 1 , wherein for the staple according to Formula (a) X is —C(O)NH—.

6. The stapled peptide of claim 1 , wherein the stapled peptide has a helical structure.

7. The stapled peptide of claim 1 , wherein the stapled peptide has one of the following structures:

8. The stapled peptide of claim 1 , wherein the stapled peptide is water soluble.

9. A method for preparation of a stapled peptide, the method comprising:
(a) reacting a first amino acid that is functionalized with a salicylaldehyde ester side group and a second amino acid functionalized with a 1,2-hydroxyl amine side group to generate an N,O-benzylidene acetal moiety, wherein the first amino acid and the second amino acid are comprised in a peptide; and
(b) performing acidolysis of the resultant N,O-benzylidene acetal moiety to generate the stapled peptide.

10. The method of claim 9 , wherein the peptide is defined according to Formula (III) or (IV):

wherein:
R is H or a C 1 -C 30 alkyl group;
X is —(CH 2 ) a — or —C(O)NH—, wherein a is an integer from 1 to 6;
m is an integer from 0 to 6;
n is an integer from 0 to 6;
[Xaa] is any natural or synthetic amino acid;
x is an integer from 2 to 10;
y is an integer from 2 to 10; and
z is an integer from 2 to 10.

11. The method of claim 10 , wherein for the peptide according to Formula (III) or Formula (IV) R is H.

12. The method of claim 10 , wherein for the peptide according to Formula (III) or Formula (IV) X is —(CH 2 ) a —.

13. The method of claim 10 , wherein for the peptide according to Formula (III) or Formula (IV) X is —C(O)NH—.

14. The method of claim 10 , wherein the stapled peptide has a helical structure.

15. A method of treating a subject in need thereof, the method comprising administering to the subject an effective amount of a stapled peptide according to claim 1 .

16. The method of claim 15 , wherein the subject presents with a viral infection.

17. The method of claim 16 , wherein the infection is an HIV infection.

18. The method of claim 16 , wherein the infection is an RSV infection.

19. The method of claim 16 , wherein the stapled peptide perturbs protein-protein interactions.

20. The method of claim 16 , wherein (a) [Xaa]y comprises the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4; or (b) the linear sequence of the peptide comprises the amino acid sequence of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9.

Assignees

• Univ Hong Kong

Inventors

• Li Xuechen
• Lee Chi-Lung
• Xu Jiaochao

Classifications

• C07K14/001

  by chemical synthesis · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K1/1075 Primary

  by covalent attachment of amino acids or peptide residues · CPC title

• C07K1/122

  Hydrolysis with acids different from HF · CPC title

• C07K7/56

  the cyclisation not occurring through 2,4-diamino-butanoic acid · CPC title