Peptide and peptidomimetic inhibitors
The present invention provides inhibitors and/or antagonists of plasma kallikrein. Also provided are methods of utilizing the inhibitors as therapeutics.
1. A method of inhibiting kallikrein activity in an eye, said method comprising delivery of a peptide to an eye of a subject, said peptide comprising an amino acid sequence having at least 80% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-239.
2. The method of claim 1 , wherein said peptide is delivered as part of a pharmaceutical composition.
3. The method of claim 2 , wherein delivery of said pharmaceutical composition is selected from one or more of topical delivery and intravitreal delivery.
4. The method of claim 3 , wherein said pharmaceutical composition comprises an implant and wherein said implant provides sustained release of said peptide.
5. The method of claim 4 , wherein said implant comprises a biodegradable polymer.
6. The method of claim 2 comprising intravitreal delivery, wherein said pharmaceutical composition is delivered by injection to a posterior section of the eye.
7. The method of claim 6 comprising sustained release of said peptide from said pharmaceutical composition.
8. The method of claim 7 , wherein said pharmaceutical composition comprises a reservoir.
9. The method of claim 7 , wherein said pharmaceutical composition comprises at least one of a microemulsion, a microsphere, a liposome, and a nanoparticle.
10. The method of claim 2 , wherein said pharmaceutical composition comprises a biodegradable polymer.
11. The method of claim 6 , wherein kallikrein activity is inhibited in at least one of the retina and the macula.
12. The method of claim 11 , wherein the subject has at least one disorder selected from one or more of retinopathy, diabetic retinopathy, macular degeneration, wet age-related macular degeneration, macular edema, diabetic macular edema, and retinal hemorrhage.
13. The method of claim 12 , wherein the subject is treated with one or more of an anti-VEGF agent, laser photocoagulation, and steroid therapy.
14. The method of claim 13 , wherein said steroid therapy comprises corticosteroid therapy.
15. The method of claim 14 , wherein said corticosteroid therapy is administered by at least one of intravitreal injection and steroid implant.
16. The method of claim 3 , wherein said pharmaceutical composition reduces at least one of vascular permeability in said eye and blood vessel leakage in said eye.
17. The method of claim 16 , wherein said peptide inhibits kallikrein activity at a half maximal inhibitory concentration (IC 50 ) of less than 100 nM.
18. The method of claim 16 , wherein said peptide is cyclic.
19. The method of claim 16 , wherein said peptide comprises a compound selected from the group consisting of R2001-R2239.
20. The method of claim 19 , wherein said intravitreal delivery comprises at least one of:
an implant comprising said pharmaceutical composition; and
an intravitreal injection comprising said pharmaceutical composition.
21. The method of claim 20 , wherein said pharmaceutical composition is delivered to a posterior section of the eye.
22. The method of claim 21 comprising sustained release of said compound from said pharmaceutical composition.
23. The method of claim 22 , wherein kallikrein activity is inhibited in at least one of the retina and the macula.
24. The method of claim 23 , wherein the subject has at least one disorder selected from one or more of retinopathy, diabetic retinopathy, macular degeneration, wet age-related macular degeneration, macular edema, diabetic macular edema, and retinal hemorrhage.
25. The method of claim 19 , wherein the compound comprises a polyethylene glycol moiety.