p21 peptides
The present invention relates to p21 derived peptides capable of inhibiting CDK/cyclin complexes, particularly cyclins A or E/CDK2, by modifying the interaction with their substrates. The peptides are derived from a C-terminal region of p21 and display selectivity for cyclin/CDK2 inhibition over cyclin/CDK4 inhibition. Variants of such peptides particularly involving certain alanine replacements are shown to be particularly potent.
1. A peptide consisting of the formula III or IV:
H′X 2 K′R 1 R 2 L′X 5 F (formula III) (SEQ ID No. 175) or H′X 2 K′R 1 R 2 L′FX 5 (formula IV) (SEQ ID No. 176),
wherein
H′ is nothing, His, D-His, Ala, Thi, Hse, Phe, or Dab;
X 2 is Ala, Ser, Abu, Val;
K′ is Lys, Arg, or Abu;
R 1 is Arg, Lys, or Gln;
R 2 forms a cyclic peptide with the C-terminal residue and is either Orn or Lys;
L′ is Leu or Ile;
X 5 is Ile, Leu, Gly, or Ala; and
F′ is Phe, para-fluoroPhe, meta-fluoroPhe, L-Psa, 2-Nap, Dhp, or D-Psa.
2. The peptide according to claim 1 , wherein X 2 is Ala.
3. The peptide of claim 1 wherein X 5 is Gly.
4. A peptide consisting of the formula IV:
H′X 2 K′R 1 R 2 L′FX 5 (formula IV) (SEQ ID NO. 176)
wherein:
H′ is nothing, His, D-His, Ala, Thi, Hse, Phe, or Dab;
X 2 is Ala, Ser, Abu, Val;
K′ is Lys, Arg or Abu;
R 1 is Arg, Lys or Gln;
R 2 is Orn or Lys;
L′ is Leu or Ile;
X 5 is Ile, Leu Gly or Ala; and
F is Phe, para-fluoro-Phe, meta-fluoro-Phe, L-Psa, 2-Nap, Dhp, or D-Psa;
and wherein said peptide is in cyclic form by virtue of a linkage between the C-terminal residue and the residue 3 upstream to it.
5. The peptide according to claim 4 wherein X 2 is Ala.
6. The peptide according to claim 4 wherein X 5 is Gly.
7. The peptide according to claim 4 wherein F is para-fluoro-Phe and H′ is alanine or nothing.
8. A peptide 5,8-cyclo-[H-His-Ala-Lys-Arg-Lys-Leu-Phe-Gly] (SEQ ID NO: 173).
9. A peptide 5,8-cyclo-[H-His-Ala-Lys-Arg-Orn-Leu-Phe-Gly] (SEQ ID NO: 174).