US2007042403A1PendingUtilityA1

Specific inhibitors of NFAT activation by calcineurin and their use in treating immune-related diseases

Assignee: HOGAN PATRICK GPriority: Feb 12, 1998Filed: Jun 23, 2006Published: Feb 22, 2007

Est. expiryFeb 12, 2018(expired)· nominal 20-yr term from priority

Inventors:Patrick Hogan Anjana Rao Jose Aramburu

C07K 5/101A61K 38/00

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References

Claims

Abstract

Isolated peptide fragments of the conserved regulatory domain of NFAT protein capable of inhibiting protein-protein interaction between calcineurin and NFAT, or a biologically active analog thereof are described. Isolated polynucleotides and gene therapy vectors encoding such peptide fragments are also described. In addition, methods for treating immune-related diseases or conditions and methods for high throughput screening of candidate agents are described. Pharmaceutical compositions are also provided.

Claims

exact text as granted — not AI-modified

1 . An isolated peptide fragment of the conserved regulatory domain of NFAT protein capable of inhibiting protein-protein interaction between calcineurin and NFAT, or a biologically active analog thereof.

2 . The peptide fragment or biologically active analog thereof of claim 1 , further being capable of inhibiting dephosphorylation of said NFAT by said calcineurin.

3 . The peptide fragment or biologically active analog thereof of claim 2 , further being capable of inhibiting a conformational change in said NFAT that results from said dephosphorylation of said NFAT by said calcineurin.

4 . The peptide fragment or biologically active analog thereof of claim 1 , further being capable of inhibiting recruitment of said NFAT to the nucleus in a cell.

5 . The peptide fragment or biologically active analog thereof of claim 1 , further being capable of inhibiting a conformational change in said NFAT that results from said protein-protein interaction between said NFAT and said calcineurin.

6 . The peptide fragment or biologically active analog thereof of claim 1 , further being capable of inhibiting NFATdependent gene transcription.

7 . The peptide fragment or biologically active analog thereof of claim 1 wherein said fragment or biologically active analog thereof does not inhibit the activity of calcineurin toward non-NFAT calcineurin substrates.

8 . The peptide fragment of claim 1 wherein said conserved regulatory domain of NFAT protein is selected from the group consisting of NFAT1, NFAT2, NFAT3 and NFAT4.

9 . The peptide fragment of claim 1 wherein said conserved regulatory domain of NFAT protein is human or murine.

10 . The peptide fragment of claim 1 wherein said interaction between said calcineurin and said NFAT is between said calcineurin and a member selected from the group consisting of NFAT1, NFAT2, NFAT3 and NFAT4.

11 . The peptide fragment of claim 1 wherein said fragment is less than about 150 amino acid residues in length.

12 . The peptide fragment of claim 1 wherein said fragment is less than about 100 amino acid residues in length.

13 . The peptide fragment of claim 1 wherein said fragment is less than about 50 amino acid residues in length.

14 . The peptide fragment of claim 1 wherein said fragment is less than about 30 amino acid residues in length.

15 . The peptide fragment of claim 1 wherein said fragment is less than about 20 amino acid residues in length.

16 . The peptide fragment of claim 1 wherein said fragment is less than about 10 amino acid residues in length.

17 . The peptide fragment of claim 1 wherein said fragment is less than about 6 amino acid residues in length.

18 . The peptide fragment of claim 1 wherein said fragment is greater than about 3 amino acid residues in length.

19 . The peptide fragment of claim 1 wherein said fragment comprises the amino acid sequence IX 2 X 3 T (SEQ ID NO:104) and wherein X 2 is E, R or Q, and X 3 is I or F.

20 . The peptide fragment of claim 19 wherein said fragment comprises the amino acid sequence IEIT (SEQ ID NO:105).

21 . The peptide fragment of claim 19 wherein said fragment comprises the amino acid sequence IRIT (SEQ ID NO:106).

22 . The peptide fragment of claim 19 wherein said fragment comprises the amino acid sequence IQIT (SEQ ID NO:107).

23 . The peptide fragment of claim 19 wherein said fragment comprises the amino acid sequence IQFT (SEQ ID NO:108).

24 . The peptide fragment of claim 1 wherein said fragment comprises the amino acid sequence X 1 IX 2 X 3 T (SEQ ID NO:73) and wherein X 1 is R or S, X 2 is E, R or Q, and X 3 is I or F.

25 . The peptide fragment of claim 24 wherein said fragment comprises the amino acid sequence X 1 IX 21 T (SEQ ID NO:74).

26 . The peptide fragment of claim 25 wherein said fragment comprises the amino acid sequence RIX 2 IT (SEQ ID NO:75).

27 . The peptide fragment of claim 25 wherein said fragment comprises the amino acid sequence X 1 IEIT (SEQ ID NO:76).

28 . The peptide fragment of claim 24 wherein said fragment comprises the amino acid sequence RIEIT (SEQ ID NO:1).

29 . The peptide fragment of claim 24 wherein said fragment comprises the amino acid sequence SIRIT (SEQ ID NO:2).

30 . The peptide fragment of claim 24 wherein said fragment comprises the amino acid sequence SIQIT (SEQ ID NO:3).

31 . The peptide fragment of claim 24 wherein said fragment comprises the amino acid sequence SIQFT (SEQ ID NO:4).

32 . The peptide fragment of claim 24 wherein said fragment comprises the amino acid sequence PX 1 IX 2 X 3 T (SEQ ID NO:77).

33 . The peptide fragment of claim 32 comprises the amino acid sequence selected consisting of:

PRIEIT,
(SEQ ID NO:5)

PSIRIT,
(SEQ ID NO:6)

PSIQIT,
(SEQ ID NO:71)

and

PSIQFT.
(SEQ ID NO:7)

34 . The peptide fragment of claim 32 wherein said fragment from the group wherein said fragment comprises the amino acid sequence X 5 PX 1 IX 2 X 3 T (SEQ ID NO:78), and wherein X5 is S or C.

35 . The peptide fragment of claim 32 wherein said fragment comprises the amino acid sequence consisting of:

SPRIEIT,
(SEQ ID NO:8)

CPSIRIT,
(SEQ ID NO:9)

CPSIQIT,
(SEQ ID NO:10)

and

CPSIQFT.
(SEQ ID NO:11)

36 . The peptide fragment of claim 34 wherein said fragment comprises the amino acid sequence X 5 PX 1 IX 2 X 3 TX 6 (SEQ ID NO:79), and wherein X 6 is P or S.

37 . The peptide fragment of claim 36 wherein said fragment selected from the group comprises the amino acid sequence selected from the group consisting of:

SPRIEITP,
(SEQ ID NO:12)

SPRIEITS,
(SEQ ID NO:13)

CPSIRITS,
(SEQ ID NO:14)

CPSIQITS,
(SEQ ID NO:15)

and

CPSIQFTS.
(SEQ ID NO:16)

38 . The peptide fragment of claim 36 wherein said fragment Comprises the amino acid sequence X 5 PX 1 IX 2 X 3 TX 6 X 7 (SEQ ID NO:80), and wherein said X 7 is S, C or I.

39 . The peptide fragment of claim 38 wherein said fragment comprises the amino acid sequence selected from the group consisting of:

SPRIEITPS,
(SEQ ID NO:17)

SPRIEITSC,
(SEQ ID NO:18)

CPSIRITSI,
(SEQ ID NO:19)

CPSIQITSI,
(SEQ ID NO:20)

and

CPSIQFTSI.
(SEQ ID NO:21)

40 . The peptide fragment of claim 38 wherein said fragment comprises the amino acid sequence X 11 X 10 X 9 X 5 PXI 1 X 2 X 3 TX 6 X 7 X 8 (SEQ ID NO:81), and wherein X 8 is H, L or S; X 9 is P, LorE; X 10 is G, L or F; and X 11 is S, A, V or P.

41 . The peptide fragment of claim 40 wherein said fragment comprises the amino acid sequence selected from the group consisting of:

SGPSPRIEITPSH,
(SEQ ID NO:22)

SGLSPRIEITPSH,
(SEQ ID NO:23)

ALESPRIEITSCL,
(SEQ ID NO:24)

VLECPSIRITSIS,
(SEQ ID NO:25)

PFECPSIQITSIS,
(SEQ ID NO:26)

PFECPSIQITSIS,
(SEQ ID NO:27)

and

PFECPSIQFTSIS.
(SEQ ID NO:28)

42 . The peptide fragment of claim 40 wherein said fragment comprises the amino acid sequence selected from the group consisting of:

KPAGASGPSPRIEITPSHELMQAGG,
(SEQ ID NO:29)

KPAGASGLSPRIEITPSHELIQAVG,
(SEQ ID NO:30)

PDGAPALESPRIEITSCLGLYHNNN,
(SEQ ID NO:31)

AGGGRVLECPSIRITSISPTPEPPA,
(SEQ ID NO:32)

LGGPKPFECPSIQITSISPNCHQEL,
(SEQ ID NO:33)

LGGPKPFECPSIQITSISPNCHQGT,
(SEQ ID NO:34)

and

LGGPKPFECPSIQFTSISPNCQQEL.
(SEQ ID NO:35)

43 - 144 . (canceled)

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