Peptide inhibitors of transcription factor aggregation

1. A peptide comprising any of

(SEQ ID NO: 10)

LTRITYH,

(SEQ ID NO: 11)

IRIRHYR,

(SEQ ID NO: 12)

IRIRRYR,

(SEQ ID NO: 13)

IRIRAYR,

(SEQ ID NO: 14)

LRIRYWK,

(SEQ ID NO: 15)

IRIRRAR,

(SEQ ID NO: 16)

IRIARYR,

(SEQ ID NO: 17)

IRIRRYA,

(SEQ ID NO: 18)

IRIYRYK,

(SEQ ID NO: 19)

TRIRFYR,

(SEQ ID NO: 20)

Ac-IRIRRYR-NH2,

(SEQ ID NO: 21)

LYIRYLR,

(SEQ ID NO: 22)

LRIKYHR,

(SEQ ID NO: 23)

IAIRRYR,

(SEQ ID NO: 24)

LRIRRYR,

(SEQ ID NO: 25)

LWIKYHR,

(SEQ ID NO: 26)

IRIRRWR,

(SEQ ID NO: 27)

LRIYRVR,

(SEQ ID NO: 28)

WTIKLWH,

(SEQ ID NO: 29)

LRIRFFR,

(SEQ ID NO: 30)

LTIRYYK,

(SEQ ID NO: 31)

YRLRYLR,

(SEQ ID NO: 32)

LFRYYQK,

(SEQ ID NO: 38)

LRLRHYR,

(SEQ ID NO: 39)

LYIKYHR,

(SEQ ID NO: 40)

YTRITYH,

(SEQ ID NO: 41)

LRIYHHK,

(SEQ ID NO: 42)

IRLRRYR,

(SEQ ID NO: 43)

YRLRYVR,

(SEQ ID NO: 48)

LTIRLWH,

(SEQ ID NO: 50)

WTIRYYK,

(SEQ ID NO: 52)

LFIKYHR,

(SEQ ID NO: 53)

TRIYRYK,

(SEQ ID NO: 54)

WTIRYYH,

(SEQ ID NO: 55)

LAIKYHR,

(SEQ ID NO: 57)

LTIKLWH,

(SEQ ID NO: 60)

LRIRHVK,

(SEQ ID NO: 62)

IRIRRAA,

(SEQ ID NO: 65)

WYIRLWK,

(SEQ ID NO: 66)

IYIYHQR,

(SEQ ID NO: 69)

WYIRLWH,

(SEQ ID NO: 80)

TYIRYLR,

(SEQ ID NO: 84)

LFIYYQR,

(SEQ ID NO: 86)

IRIRAAR,

(SEQ ID NO: 91)

YYIRYYK,

(SEQ ID NO: 93)

WRIRRYR,

(SEQ ID NO: 107)

IWIRRWR,

(SEQ ID NO: 110)

TRIYRVK,

and

(SEQ ID NO: 111)

TYIYRQR,

or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.

2. A peptide of claim 1 that is capable of inhibiting aggregation of p53 and/or p63 and/or p73.

3. A peptide of claim 1 comprising any of

(SEQ ID NO: 11)

IRIRHYR,

(SEQ ID NO: 12)

IRIRRYR,

(SEQ ID NO: 14)

LRIRYWK,

(SEQ ID NO: 18)

IRIYRYK,

(SEQ ID NO: 19)

TRIRFYR,

(SEQ ID NO: 28)

WTIKLWH,

(SEQ ID NO: 29)

LRIRFFR,

and

(SEQ ID NO: 38)

LRLRHYR,

or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.

4. A peptide comprising an amino acid sequence of Formula Ia':

(Ia′)

(SEQ ID NO: 202)

(Arg) n -Pro-Ile-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-

Xaa8

wherein

n is a number between 1 and 16 , inclusive;

Xaa1 is Ile, Leu, Trp, Thr, or Tyr;

Xaa2 is Arg, Phe, Trp, Thr, Ala, or Tyr;

Xaa3 is Ile, Arg, or Leu;

Xaa4 is Arg, Lys, Ala, Tyr;

Xaa5 is His, Arg, Tyr, Leu, Ala, or Phe;

Xaa6 is Tyr, Ala, Gln, Leu, Val, His, Trp, or Phe;

Xaa7 is Arg, Ala, His, or Lys; and

Xaa8 is absent;

provided the sequence Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8 is not YRIRRYR (SEQ ID NO: 219), IRIAAYR (SEQ ID NO: 221), IRIARAR (SEQ ID NO: 222), IRIARYA (SEQ ID NO: 223) or IRIRAYA (SEQ ID NO: 224);

or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.

5. The peptide of claim 4 comprising RRRRRRRRRRPIIRIRHYR (SEQ ID NO: 203); or C-terminal acids and amides thereof, or N-acetyl derivatives thereof;

or pharmaceutically acceptable salts thereof.

6. The peptide of claim 1 , wherein the peptide further comprises a duration enhancing moiety, and optionally further comprises a linker attaching the peptide to the duration enhancing moiety; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.

7. The peptide of claim 1 , wherein the peptide is attached to a cell penetrating peptide (CPP); or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition comprising a peptide of claim 2 and a pharmaceutically acceptable carrier.

9. A method of treating cancer with a peptide of claim 2 that is capable of inhibiting aggregation of p53, the method comprising administering the peptide to a patient with the cancer, wherein the cancer is characterized by aberrantly folded or aggregated p53.

10. The method according to claim 9 that comprises administering a composition that comprises the peptide and a pharmaceutically acceptable carrier to the patient.

11. The method of claim 9 , wherein the cancer is ovarian cancer.

12. A method of affecting p53 aggregation comprising contacting cells or treatment of a patient with a peptide of claim 6 that is capable of inhibiting aggregation of p53.

13. The method of claim 9 , wherein the cancer is nasopharyngeal cancer.

14. The peptide according to claim 1 that is less than 25 amino acids in length.

15. The peptide according to claim 2 that is less than 25 amino acids in length.

16. A method of affecting p63 aggregation comprising contacting cells or treatment of a patient with a peptide of claim 2 that is capable of inhibiting aggregation of p63.

17. A method of affecting p73 aggregation comprising contacting cells or treatment of a patient with a peptide of claim 2 that is capable of inhibiting aggregation of p73.

18. A peptide of claim 13 that is capable of inhibiting aggregation of p53 and/or p63 and/or p73.

19. A pharmaceutical composition comprising a peptide of claim 18 and a pharmaceutically acceptable carrier.

20. A method of treating cancer with a peptide of claim 18 that is capable of inhibiting aggregation of p53, the method comprising administering the peptide to a patient with the cancer, wherein the cancer is characterized by aberrantly folded or aggregated p53.

21. The method according to claim 20 that comprises administering a composition that comprises the peptide and a pharmaceutically acceptable carrier to the patient.

22. A pharmaceutical composition comprising a peptide of claim 7 and a pharmaceutically acceptable carrier.