Selective substrates for matrix metalloproteinases
The invention provides isolated MMP-2, MMP-9 and MT1-MMP selective substrate polypeptides or functional peptidomimetics. The selective substrate polypeptides contain the following sequences: MMP-2 selective substrate polypeptides contain SEQ ID NOS:1-27, MMP-9 selective substrate polypeptides contain SEQ ID NOS:28-35, and MT1-MMP selective substrate polypeptide contain SEQ ID NOS:36-40. In addition, the invention provides a method of preferentially directing a moiety to a site of MMP-2 activity by administering to a subject an effective amount of an isolated MMP-2 selective substrate polypeptide containing SEQ ID NOS:45-47 linked to a moiety. Also provided is a method of preferentially directing a moiety to a site of MMP-9 activity by administering to a subject an effective amount of an isolated MMP-9 selective substrate polypeptide containing SEQ ID NO:44 linked to a moiety, and preferentially directing a moiety to a site of MT1-MMP activity by administering to a subject an effective amount of an isolated MT1-MMP selective substrate polypeptide containing SEQ ID NOS:36-40 linked to a moiety.
1. An isolated matrix metalloproteinase-2 (MMP-2) selective substrate polypeptide, comprising the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-7 and 9, wherein said MMP-2 selective substrate polypeptide has 100 or fewer amino acids and can be hydrolyzed by MMP-2.
2. The isolated MMP-2 selective substrate of claim 1 , wherein said MMP-2 selective substrate polypeptide has 40 or fewer amino acids.
3. The isolated MMP-2 selective substrate of claim 1 , wherein said MMP-2 selective substrate polypeptide has 20 or fewer amino acids.
4. The isolated MMP-2 selective substrate of claim 1 , wherein said MMP-2 selective substrate polypeptide has 10 or fewer amino acids.
5. The isolated MMP-2 selective substrate polypeptide of claim 1 , wherein said amino acid sequence is SEQ ID NO:1.
6. The isolated MMP-2 selective substrate polypeptide of claim 1 , wherein said amino acid sequence is SEQ ID NO:2.
7. The isolated MMP-2 selective substrate polypeptide of claim 1 , wherein said amino acid sequence is SEQ ID NO:3.
8. The isolated MMP-2 selective substrate polypeptide of claim 1 , wherein said amino acid sequence is SEQ ID NO:4.
9. The isolated MMP-2 selective substrate polypeptide of claim 1 , wherein said amino acid sequence is SEQ ID NO:5.
10. The isolated MMP-2 selective substrate polypeptide of claim 1 , wherein said amino acid sequence is SEQ ID NO:6.
11. The isolated MMP-2 selective substrate polypeptide of claim 1 , wherein said amino acid sequence is SEQ ID NO:7.
12. The isolated MMP-2 selective substrate polypeptide of claim 1 , wherein said amino acid sequence is SEQ ID NO:9.
13. An isolated matrix metalloproteinase-2 (MMP-2) selective substrate polypeptide, consisting of the amino acid sequence selected from the group consisting of SEQ ID NOS 1-9, wherein said MMP-2 selective substrate polypeptide can be hydrolyzed by MMP-2.
14. The isolated MMP-2 selective substrate polypeptide of claim 13 , wherein said amino acid sequence is SEQ ID NO:1.
15. The isolated MMP-2 selective substrate polypeptide of claim 13 , wherein said amino acid sequence is SEQ ID NO:2.
16. The isolated MMP-2 selective substrate polypeptide of claim 13 , wherein said amino acid sequence is SEQ ID NO:3.
17. The isolated MMP-2 selective substrate polypeptide of claim 13 , wherein said amino acid sequence is SEQ ID NO:4.
18. The isolated MMP-2 selective substrate polypeptide of claim 13 , wherein said amino acid sequence is SEQ ID NO:5.
19. The isolated MMP-2 selective substrate polypeptide of claim 13 , wherein said amino acid sequence is SEQ ID NO:6.
20. The isolated MMP-2 selective substrate polypeptide of claim 13 , wherein said amino acid sequence is SEQ ID NO:7.
21. The isolated MMP-2 selective substrate polypeptide of claim 13 , wherein said amino acid sequence is SEQ ID NO:8.
22. The isolated MMP-2 selective substrate polypeptide of claim 13 , wherein said amino acid sequence is SEQ ID NO:9.
23. The isolated MMP-2 selective substrate polypeptide of claim 13 , wherein said polypeptide is linked to a moiety.
24. The isolated MMP-2 selective substrate polypeptide of claim 23 , wherein said moiety is a diagnostic agent.
25. The isolated MMP-2 selective substrate polypeptide of claim 24 , wherein said diagnostic agent is a quenched fluorophore.
26. The isolated MMP-2 selective substrate polypeptide of claim 23 , wherein said moiety is a therapeutic moiety.
27. The isolated MMP-2 selective substrate polypeptide of claim 26 , wherein said therapeutic moiety is a chemotherapeutic agent.
28. The isolated MMP-2 selective substrate polypeptide of claim 26 , wherein said therapeutic moiety is selected from the group consisting of an anti-angiogenic agent, a pro-angiogenic agent and an agent that promotes tissue repair.
29. A fusion protein comprising a polypeptide fused to a matrix metalloproteinase-2 (MMP-2) selective substrate polypeptide consisting of the amino acid sequence selected from the group consisting of SEQ ID NO: 1-9, wherein said MMP-2 selective substrate polypeptide can be hydrolyzed by MMP-2.
30. The fusion protein of claim 29 , wherein said amino acid sequence is SEQ ID NO:1.
31. The fusion protein of claim 29 , wherein said amino acid sequence is SEQ ID NO:2.
32. The fusion protein of claim 29 , wherein said amino acid sequence is SEQ ID NO:3.
33. The fusion protein of claim 29 , wherein said amino acid sequence is SEQ ID NO:4.
34. The fusion protein of claim 29 , wherein said amino acid sequence is SEQ ID NO:5.
35. The fusion protein of claim 29 , wherein said amino acid sequence is SEQ ID NO:6.
36. The fusion protein of claim 29 , wherein said amino acid sequence is SEQ ID NO:7.
37. The fusion protein of claim 29 , wherein said amino acid sequence is SEQ ID NO:8.
38. The fusion protein of claim 29 , wherein said amino acid sequence is SEQ ID NO:9.