Stitched polypeptides

Patent metadata

Field	Value
Publication number	US-10301351-B2
Application number	US-201615275118-A
Country	US
Kind code	B2
Filing date	Sep 23, 2016
Priority date	Mar 28, 2007
Publication date	May 28, 2019
Grant date	May 28, 2019

Abstract

The present invention provides inventive stitched polypeptides, pharmaceutical compositions thereof, and methods of making and using inventive stitched polypeptides.

First claim

We claim:

1. A method of preparing an alpha-helical polypeptide, said method comprising the steps of:
(i) providing an amino acid of Formula (A):

or a salt thereof;
(ii) providing an amino acid of the Formula (B):

or a salt thereof;
(iii) providing an amino acid of the Formula (C):

or a salt thereof;
(iv) providing at least one additional amino acid;
(v) coupling said amino acids of Formulae (A), (B), and (C) with at least one amino acid of step (iv); and
(vi) treating the polypeptide of step (v) with a catalyst;

wherein
each instance of L 1 and L 2 is, independently, a straight chain alkylene of 1 to 7 carbon atoms;
K is a straight chain alkylene of 1 to 7 carbon atoms;
M is a straight chain alkylene of 1 to 7 carbon atoms;
each instance of R a is, independently, hydrogen; cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; cyclic or acyclic, substituted or unsubstituted acyl; or an amino protecting group;
R b is hydrogen; cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic;
each instance of R c , is, independently, hydrogen; cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; cyclic or acyclic, substituted or unsubstituted acyl; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; cyano; isocyano; halo; or nitro;
each instance of R e is, independently, —R E , wherein each instance of —R E is, independently, hydrogen, cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; a resin; or a hydroxyl protecting group;
each instance of R f is, independently, hydrogen; cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; a resin; an amino protecting group; or a label optionally joined by a linker, wherein the linker is selected from cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkenylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkynylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkenylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkynylene; substituted or unsubstituted arylene; substituted or unsubstituted heteroarylene; or substituted or unsubstituted acylene;
or R f and R a together form a substituted or unsubstituted heterocyclic or heteroaromatic ring; and
each instance of x is, independently, an integer between 0 to 3, inclusive.

2. The method of claim 1 , wherein said catalyst is a ring closing metathesis catalyst.

3. The method of claim 1 , wherein said catalyst is a ruthenium catalyst.

4. The method of claim 1 , wherein each R a is hydrogen or methyl.

5. The method of claim 1 , wherein each R a is hydrogen.

6. The method of claim 1 , wherein at least one R a is —COCH 3 .

7. The method of claim 1 , wherein each W is alkyl.

8. The method of claim 1 , wherein each R b is methyl.

9. The method of claim 1 , wherein each R f is hydrogen.

10. The method of claim 1 , wherein each R e is hydrogen.

11. The method of claim 1 , wherein each R f is an amino protecting group.

12. The method of claim 1 , wherein each R f is Boc.

13. The method of claim 1 , wherein each R f is Fmoc.

14. The method of claim 1 , wherein each is a double bond.

15. The method of claim 1 , wherein the amino acid of Formula (A) is an amino acid of Formula (A-2):

16. The method of claim 15 , wherein the amino acid of Formula (A-2) is of one of the following formulae:

17. The method of claim 1 , wherein an amino acids of Formulae (B) and (C) are independently of one of the following formulae:

18. The method of claim 1 , wherein an amino acids of Formulae (B) and (C) are independently of one of the following formulae:

Assignees

• Harvard College

Inventors

• Verdine Gregory L
• Kim Young-Woo

Classifications

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P5/18

  of the parathyroid hormones · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title