Peptides and peptidomimetics with structural similarity to human p53 that activate p53 function
View Patent ↗The present invention provides peptides and peptidomimetics corresponding to part or to the entirety of the region encompassed by residues 360-386 of human p53, said peptides and peptidomimetics characterized by the ability to activate DNA binding of wild-type p53 and of select tumor-derived p53 mutants. Pharmaceutical compositions of the compounds of the invention and methods of using these compositions therapeutically are also provided.
1. A peptidomimetic of a peptide which competes with an endogenous p53 negative regulatory region for binding with a negative regulatory region NRR1 comprising residues 361-383 of p53 or NRR2 comprising residues 300-321 of p53, said peptide containing at least four sequential amino acids from a negative regulatory region which maps to residues 361-383 (SEQ ID NO. 2) of p53, said peptide not being a subfragment of human p53, wherein said peptide activates, in a p53 DNA binding assay, DNA binding of wild-type p53 or a p53 mutant.
2. The peptidomimetic of claim 1 , wherein said p53 mutant contains a single amino acid substitution, said p53 mutant selected from the group consisting of p53-ser 239 , p53-his 273 , p53-gln 248 , p53-trp 282 , and p53-cys 273 .
3. The peptidomimetic of claim 2 , wherein said p53 mutant is p53-ser 239 .
4. The peptidomimetic of claim 2 , wherein said p53 mutant is p53-his 273 .