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 peptide comprising SEQ ID NO: 2 or an amino acid sequence having at least 80% homology to SEQ ID NO: 2.
2. The peptide of claim 1 , wherein the peptide is cyclized with a reagent, thereby forming a cyclic peptide.
3. The cyclic peptide of claim 2 , wherein the reagent is a thiol-reactive reagent.
4. The cyclic peptide of claim 3 , wherein the thiol-reactive reagent is selected from the group consisting of: 1,2-bis(bromomethyl)benzene, 1,4-bis(bromomethyl)benzene, 2,6-bis(bromomethyl)pyridine, substituted bis(bromomethyl)benzenes and (E)-1,4-dibromobut-2-ene.
5. The cyclic peptide of claim 2 , wherein the thiol-reactive reagent is 1,3-bis(bromomethyl)benzene.
6. The cyclic peptide of claim 2 , wherein a loop is formed between two cysteine residues located at position 2 and position 6 of the cyclic peptide.
7. A method for the treatment of hereditary angioedema in a subject comprising the administration to said subject in need thereof of a therapeutically effective amount of a serine protease inhibitor, characterized in that the serine protease is plasma kallikrein and the serine protease inhibitor is a peptide or peptide mimetic comprising the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having 80% homology to SEQ ID NO: 2.
8. The method of claim 7 , wherein administration is selected from the group consisting of oral, intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, and intravitreal.
9. The method of claim 8 , wherein the inhibitor of plasma kallikrein is conjugated to a water soluble polymer.
10. The method of claim 9 , wherein the water soluble polymer is a hydrophilic polymer.
11. The method of claim 10 , wherein the hydrophilic polymer is selected from the group consisting of polyalkylene oxide homopolymers, polypropylene glycols, polyoxyethylenated polyols, and copolymers thereof.
12. The method of claim 11 , wherein the water soluble polymer is polyethylene glycol (PEG).
13. A pharmaceutical composition comprising the cyclic peptide of claim 3 and a pharmaceutically acceptable carrier or excipient.
14. The cyclic peptide of claim 2 , having kallikrein inhibitory activity with an IC 50 of less than 100 nM.
15. The cyclic peptide of claim 14 having an IC 50 of less than 50 nM against human kallikrein.
16. The cyclic peptide of claim 15 having an IC 50 of less than 10 nM against human kallikrein.
17. The cyclic peptide of claim 2 , comprising one or more unnatural amino acids.
18. The cyclic peptide of claim 17 , having kallikrein inhibitory activity and comprising at least one peptidic bond replacement, said at least one peptidic bond replacement being with a non-peptide moiety.
19. The cyclic peptide of claim 18 , wherein the non-peptide moiety is selected from the group consisting of thioamide, sulfonamide, sulfonate, phosphonamide, phosphonate phosphothioate, phosphinate, alkane, 1 or 2 hydroxyethylene, dihydroxylethylene, C—C single bond (alkane), C—C double bond (alkene), C—C triple bond (alkyne), C—O bond (methyleneoxy), O—N or N—O bond, (methylenemino), triazole, hydrazide, urea, ketone, urethane bond, (di)haloalkene, methylenemercapto, methyleneamino, trifluoroethylamino, hydrazide and amideoxy.
20. The method of claim 7 , wherein the method further comprises administering one or more additional inhibitors of plasma kallikrein.