Stabilized compounds having secondary structure motifs

Patent metadata

Field	Value
Publication number	US-9505801-B2
Application number	US-201314068844-A
Country	US
Kind code	B2
Filing date	Oct 31, 2013
Priority date	May 18, 1999
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

The present invention provides novel stabilized crosslinked compounds having secondary structure motifs, libraries of these novel compounds, and methods for the synthesis of these compounds libraries thereof. The synthesis of these novel stabilized compounds involves (1) synthesizing a peptide from a selected number of natural or non-natural amino acids, wherein the peptide comprises at least two moieties capable of undergoing reaction to promote carbon-carbon bond formation; and (2) contacting the peptide with a reagent to generate at least one crosslinker and to effect stabilization of a secondary structure motif. The present invention, in a preferred embodiment, provides stabilized p53 donor helical peptides. Additionally, the present invention provides methods for disrupting the p53/MDM2 binding interaction comprising (1) providing a crosslinked stabilized α-helical structure; and (2) contacting the crosslinked stabilized α-helical structure with MDM2.

First claim

We claim:

1. A method for disrupting the binding of a p53 protein to an MDM2 protein, the method comprising contacting a peptide with the MDM2 protein, wherein the peptide comprises at least two amino acids connected by a hydrocarbon covalent cross-link that stabilizes a secondary structure an α-helix of the peptide.

2. The method of claim 1 , further comprising contacting the peptide with the p53 protein.

3. The method of claim 1 , wherein the peptide comprises an MDM2 binding site of a p53 donor helix.

4. The method of claim 1 , wherein the cross-link comprises a carbon-carbon double bond.

5. The method of claim 1 , wherein at least one amino acid in the peptide is a non-natural amino acid.

6. The method of claim 1 , wherein the at least two amino acids in the peptide comprise olefins.

7. The method of claim 1 , wherein the at least two amino acids that are connected by the hydrocarbon covalent cross-link are alpha,alpha-methyl, vinyl; alpha, alpha-methyl, alkylolefin; or divinyl amino acids.

8. The method of claim 7 , wherein the alpha, alpha-disubstituted amino acids that are connected by the hydrocarbon covalent cross-link are positioned at i,i+4 or at i,i+7.

9. The method of claim 7 , wherein at least one amino acid that is connected by the hydrocarbon covalent cross-link comprises an alpha-methyl, alpha-alkenyl amino acid.

10. The method of claim 9 , wherein the alpha-methyl, alpha-alkenyl amino acid comprises a n-pentenyl or n-octenyl side chain.

11. The method of claim 1 , wherein the cross-link spans from one to two turns on an α-helix.

12. The method of claim 1 , wherein the length of the cross-link between the two α positions is 7 or 8 carbon atoms.

13. The method of claim 1 , wherein the length of the cross-link between the two α positions is 9 to 12 carbon atoms.

14. The method of claim 1 , wherein the length of the cross-link between the two α positions is 11 carbon atoms.

15. The method of claim 1 , wherein the cross-linked peptide exhibits increased helicity compared to an uncrosslinked peptide.

16. The method of claim 1 , wherein the cross-link is generated by a transition metal catalyzed cross-coupling reaction.

Assignees

• Harvard College

Inventors

• Verdine Gregory L
• Schafmeister Christian E

Classifications

• C07K14/001

  by chemical synthesis · CPC title

• C07K1/10

  using coupling agents {(C07K1/006 takes precedence)} · CPC title

• A61K38/02

  Peptides of undefined number of amino acids; Derivatives thereof · CPC title

• C07K1/04

  on carriers {(C07K1/003, C07K1/006 take precedence)} · CPC title

• C07K1/047 Primary

  Simultaneous synthesis of different peptide species; Peptide libraries · CPC title