Stabilized p53 peptides and uses thereof
Cross-linked peptides related to human p53 and bind to HMD2 or a family member of HDM2 useful for promoting apoptosis, e.g., in the treatment of and identifying therapeutic agents that binding to HMD2 or a family member of HDM2.
1. A peptide of Formula (I),
or a pharmaceutically acceptable salt thereof,
wherein:
each R 1 and R 2 is independently H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl;
each R 3 is independently alkyl, alkenyl, alkynyl, or [R 4 —K—R 4 ′] n , each of which is independently substituted with 0-6 R 5 ;
each R 4 and R 4 ′ is independently alkylene, alkenylene or alkynylene;
each R 5 is independently halo, alkyl, OR 6 , N(R 6 ) 2 , SR 6 , SOR 6 , SO 2 R 6 , CO 2 R 6 , R 6 , a fluorescent moiety, or a radioisotope;
each K is independently O, S, SO, SO 2 , CO, CO 2 , CONR 6 , or
each R 6 is independently H, alkyl, or a therapeutic agent;
each n is independently an integer from 1-4;
each x is 6;
each y is independently an integer from 0-100;
each w is independently an integer from 0-100;
z is an integer from 1-10; and
each Xaa is independently an amino acid;
wherein the peptide comprises 8 contiguous amino acid residues, wherein the 8 contiguous amino acid residues comprise Phe, Leu, and Trp, wherein the peptide exhibits a binding affinity for HDM 2 that is from about 0.75 nM to about 110 nM, wherein [Xaa] x prises the Leu and the Trp.
2. The peptide of claim 1 , wherein the peptide binds to HDM2.
3. The peptide of claim 1 , wherein each R 3 is independently an alkenylene group.
4. The peptide of claim 1 , wherein each R 3 is independently an alkylene group.
5. The peptide of claim 1 , wherein each R 1 and each R 2 is independently alkyl.
6. The peptide of claim 1 , wherein each R 1 and each R 2 is methyl.
7. The peptide of claim 1 , wherein each R 1 and each R 2 is H.
8. The peptide of claim 1 , wherein z is 1.
9. The peptide of claim 1 , wherein each w is independently an integer from 3 to 15.
10. The peptide of claim 1 , wherein each y is independently an integer from 3 to 15.
11. The peptide of claim 1 , wherein the peptide is permeable to a cell membrane.
12. The peptide of claim 1 , wherein the peptide comprises a helix.
13. The peptide of claim 1 , wherein the peptide comprises an α-helix.
14. The peptide of claim 13 , wherein R 3 extends across the length of one helical turn.
15. The peptide of claim 13 , wherein R 3 extends across the length of two helical turns.