Proline-locked stapled peptides and uses thereof

Patent metadata

Field	Value
Publication number	US-9617309-B2
Application number	US-201314431280-A
Country	US
Kind code	B2
Filing date	Sep 26, 2013
Priority date	Sep 26, 2012
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

The present invention provides a new type of alpha-helix nucleating cross-link (“staple”) formed by olefin metathesis of a proline derivative with an alkenyl side chain and another amino acid derivative with an alkenyl side chain. The proline derivatives as described herein have been found to be strong nucleators of alpha-helix formation. The invention also provides moieties for shielding the free amide N—H's at the N-terminus of an alpha-helix, thereby further stabilizing the helix. The proline derivatives, precursors prior to cross-linking, and the cross-linked peptides are provided as well as methods of using and preparing these compounds and peptides.

First claim

What is claimed is:

1. A polypeptide of Formula (I):

or a salt or stereoisomer thereof;
wherein:
each instance of K and L, is, independently, a bond or a group consisting of one or more combinations of substituted or unsubstituted alkylene; substituted or unsubstituted alkenylene; substituted or unsubstituted alkynylene; substituted or unsubstituted heteroalkylene; substituted or unsubstituted heteroalkenylene; substituted or unsubstituted heteroalkynylene; substituted or unsubstituted heterocyclene, substituted or unsubstituted carbocyclene, substituted or unsubstituted arylene; substituted or unsubstituted heteroarylene;
R a is hydrogen; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; a resin; an amino protecting group; a label optionally joined by a linker, wherein the linker is a group consisting of one or more combinations of substituted or unsubstituted alkylene; substituted or unsubstituted alkenylene; substituted or unsubstituted alkynylene; substituted or unsubstituted heteroalkylene; substituted or unsubstituted heteroalkenylene; substituted or unsubstituted carbocyclene; substituted or unsubstituted heterocyclene; substituted or unsubstituted arylene; or substituted or unsubstituted heteroarylene;
R b is, —R B , —OR B , —N(R B ) 2 , or —SR B , wherein each instance of R B is, independently, hydrogen; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; a resin; a suitable hydroxyl, amino protecting group; or two R B groups together form a substituted or unsubstituted 5- to 6-membered heterocyclic or heteroaromatic ring;
each instance of R KL is, independently, hydrogen; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; azido; cyano; isocyano; halo; or nitro;
each instance of R d is, independently, hydrogen; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; or R d is an amino protecting group;
each instance of R e is, independently, a suitable amino acid side chain; hydrogen; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; cyano; isocyano; halo; or nitro;
each instance of G is, independently, a natural or unnatural amino acid or a group of the formula:

wherein:
n is 1, 2, or 3; and
each instance of R 1 and R 2 is independently hydrogen; substituted or unsubstituted aliphatic;
substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; or halo, or R 1 and R 2 are joined to form a carbocyclic or heterocyclic ring;
each instance of R 3 and R 4 is, independently, hydrogen; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; a hydroxyl protecting group when attached to an oxygen atom, or an amino protecting group when attached to a nitrogen atom, or two R 3 groups when attached to a nitrogen atom are joined to form a heterocyclic ring;
each instance of X AA is, independently, a natural or unnatural amino acid;
j is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
p is, independently, 1 or 2;
each instance of q is independently 0, 1, or 2;
v is, independently, 0 or 1;
each instance of w and z is, independently, an integer from 0 to 100;
y is, independently, 1, 2, 3, or 4;
corresponds to a single, double or triple bond.

2. A composition comprising a polypeptide of claim 1 , and an excipient.

3. The polypeptide of claim 1 of the formula:

or a salt or stereoisomer thereof.

4. The polypeptide of claim 3 selected from any one of the formula:

or a salt or stereoisomer thereof.

5. The polypeptide of claim 1 of the formula:

or a salt or stereoisomer thereof.

6. The polypeptide of claim 5 selected from any one of the formula:

7. The polypeptide of claim 1 , wherein p is 1.

8. The polypeptide of claim 1 , wherein q is 0.

9. The polypeptide of claim 1 , wherein p is 1 and q is 0.

10. The polypeptide of claim 1 , wherein each instance of R e is, independently, hydrogen, —CH 3 , —CH 2 OH, —COOH, or —CH 2 COOH.

11. The polypeptide of claim 1 , wherein each instance of R e is —CH 3 .

12. The polypeptide of claim 1 , wherein each R d is hydrogen.

13. The polypeptide of claim 1 , wherein each instance of y is, independently, 1 to 8.

14. The polypeptide of claim 1 , wherein each instance of y is 2.

15. The polypeptide of claim 1 , wherein R a is substituted or unsubstituted acyl.

16. The polypeptide of claim 1 , wherein R a is hydrogen.

17. The polypeptide of claim 1 , wherein R b is —OR B .

18. The polypeptide of claim 1 , wherein R b is a —OH.

19. The polypeptide of claim 1 , wherein each instance of K is, independently, —CH 2 —, —(CH 2 ) 2 —, or —(CH 2 ) 3 —.

20. The polypeptide of claim 1 , wherein each instance of K is —CH 2 —.

21. The polypeptide of claim 1 , wherein each instance of L is, independently, —CH 2 —, —(CH 2 ) 2 —, or —(CH 2 ) 3 —.

22. The polypeptide of claim 1 , wherein each instance of L is —CH 2 —.

23. The polypeptide of claim 1 , wherein corresponds to a double bond.

24. The polypeptide of claim 1 , wherein each instance of R e is —CH 3 .

25. The polypeptide of claim 1 , wherein:
K and L are —CH 2 —;
R d is —H;
R e is —CH 3 ;
j is 1;
p is 1;
q is 0;
y is 2; and
corresponds to a double bond.

26. The polypeptide of claim 3 , wherein:
p is 1;
q is 0;
j is 1;
y is 2;
K is —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, or —O—(CH 2 ) 1-3 —;
L is

Assignees

• Harvard College

Inventors

• Verdine Gregory L
• Hayashi Kazuhiro

Classifications

• C07K7/56 Primary

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

• C07D207/16

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07K1/113

  without change of the primary structure · CPC title

• A61P17/10

  Anti-acne agents · CPC title

• A61P9/12

  Antihypertensives · CPC title