Claims
- 1. An inhibitor of a phosphoserine- or phosphothreonine-proline specific peptidyl-prolyl isomerase comprising a molecule that mimics the structure and conformation of the pSer/pThr-Pro peptide moiety of the isomerase substrate when the substrate is bound into the active site of the isomerase.
- 2. The inhibitor of claim 1 wherein the structure surrounding the mimic moiety is flanked on one side by hydrophobic residues and on the other side by hydrophobic or positively charged groups wherein the groups contact the active site of the isomerase.
- 3. An inhibitor of a phosphoserine- or phosphothreonine-proline specific peptidyl-prolyl isomerase comprising a protein, peptide or peptide mimetic comprising xSer/ThrY wherein x is a negatively charged tetra or pentavalent moiety and Y is a Pro or a Pro analog.
- 4. The inhibitor of claim 3 wherein x is selected from the group consisting of phosphate, sulfonate, boronate, phosphonate and sulfonyl amide.
- 5. The inhibitor of claim 3 wherein the proline analog is a nitrogen-containing ring structure selected from the group consisting of imidazole, pyrole, tropolone, benzene, camphor and heterocyclic aromatic and non-aromatic ring structures.
- 6. The inhibitor of claim 3 wherein the Kl of the inhibitor is ten micromolar or less.
- 7. The inhibitor of claim 3 wherein xSer/Thr-Y is flanked on one side by hydrophobic residues and on the other side by hydrophobic residues or positively charged residues.
- 8. The compound of claim 3 wherein the protein, peptide or peptide mimetic is linear or cyclic.
- 9. A method of inhibiting cell growth comprising inhibiting a mitotic peptidyl-prolyl isomerase in the cell comprising contacting the cell with an effective amount of the inhibitor of claim 3.
- 10. The method of claim 9 wherein the mitotic peptidyl-prolyl isomerase is Pin1.
- 11. The method of claim 9 wherein the cell is in an individual.
- 12. The method of claim 9 wherein the cell growth results from a hyperplastic or neoplastic disorder.
- 13. The method of claim 9 wherein the cells are eukaryotic cells.
- 14. The method of claim 9 wherein the cells are selected from the group consisting of: mammalian cells, yeast cells and fungal cells.
A composition comprising an inhibitor of claim 3 and a pharmaceutically-acceptable carrier.
- 16. A compound that inhibits a phosphoserine- or phospho threonine-proline specific peptidyl-prolyl isomerase comprising a protein, peptide and/or a peptide mimetic wherein said protein, peptide or peptide mimetic has a core sequence of XXXpSer-ProXXX, wherein X is any L-amino acid, or D-amino acid.
- 17. The compound of claim 16 wherein the ptrotein, peptide or peptide mimetic is about eight amino acid residues in length and comprises the sequence X1X2X3pS-PX4X5X6 wherein each residue can be independently selected as follows X1 is W, Y or F; X2 is F or I; X3 is Y, R, F or W; X4 is R, F, Y or W; X5 is L or I and X6 is any amino acid.
- 18. The compound of claim 16 wherein the inhibitor has a Kl of ten micromolar or less.
- 19. A peptide inhibitor of a phosphoserine- or phosphothreonine-proline-specific peptide prolyl isomerase comprising Trp-Phen-Tyr-pSer-Pro-Arg.
- 20. A library of peptides that comprises a mixture of substantially equimolar amounts of peptides comprising the sequence NH2-MAXXXpSXXXAKK, wherein for each peptide X is any amino acid.
- 21. A library of compounds that comprises a mixture of substantially equimolar amounts of peptides comprising the sequence X1X2X3PS-PX4X5X6, wherein for each peptide X is any amino acid.
- 22. A method of identifying a phosphorserine- or phosphothreonine-specific peptidyl prolyl isomerase inhibitor comprising the steps of:
a) providing a library of compounds that comprises a mixture of substantially equimolar amounts of peptides comprising the sequence X1X2X3pS-PX4X5X6, wherein for each peptide X is any amino acid; b) contacting the library of a) with the peptidyl prolyl isomerase of interest under binding conditions for time sufficient for the isomerase to bind to the peptides; c) determining the amino acid sequences of peptides bound to the isomerase of interest; d) synthesizing the peptides of c); and e) determining the Kl of the peptide wherein a peptide with a Kl of ten micromolar or less indicates that the peptide is suitable for use as an inhibitor of the isomerase of interest.
- 23. A method of identifying a phosphorserine- or phosphothreonine-specific peptidyl prolyl isomerase inhibitor comprising the steps of:
a) providing the peptidyl prolyl isomerase of interest; b) mixing the isomerase of interest with:
i) a candidate inhibitor molecule and ii) the substrate of the isomerase of interest to form an admixture of the isomerase of interest, candidate molecule and substrate; c) maintaining the admixture of b) under conditions sufficient for the isomerase of interest to catalyze the cis/trans isomerazation of the substrate; and d) determining the Kl of the candidate molecule, wherein a Kl of 10 micromolar or less is indicative of an inhibitor of the peptidyl prolyl isomerase of interest.
RELATED APPLICATION
[0001] This application claims priority to U.S. provisional application Serial No. 60/058,164, the entire teachings of which are incorporated herein by reference.
GOVERNMENT FUNDING
[0002] This invention was made with U.S. Government support under USPHS Grant Nos. RO1 GM56230 and GM56203. The United States government has certain rights in the invention.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60058164 |
Sep 1997 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
08988842 |
Dec 1997 |
US |
Child |
10193768 |
Jul 2002 |
US |