Claims
- 1. A method for preserving an organ or tissue comprising contacting the organ or tissue with an effective amount of a kallikrein inhibitor.
- 2. The method of claim 1, wherein the polypeptide comprises a Kunitz domain.
- 3. The method according to claim 2, wherein the kallikrein inhibitor is a polypeptide comprising SEQ ID NO:2.
- 4. The method according to claim 2, wherein the kallikrein inhibitor is a polypeptide comprising amino acids 3-60 of SEQ ID NO:2.
- 5. The method of claim 1, wherein the organ or tissue is heart, lung, kidney, pancreas, liver, intestine, endothelial tissue, vascular tissue or skin.
- 6. A method for preserving an organ or tissue comprising contacting the organ or tissue with an effective amount of a kallikrein inhibitor comprising a polypeptide comprising the amino acid sequence: Xaa1 Xaa2 Xaa3 Xaa4 Cys Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Gly Xaa13 Cys Xaa15 Xaa16 Xaa17 Xaa18 Xaa19 Xaa20 Xaa21 Xaa22 Xaa23 Xaa24 Xaa25 Xaa26 Xaa27 Xaa28 Xaa29 Cys Xaa31 Xaa32 Phe Xaa34 Xaa35 Gly Gly Cys Xaa39 Xaa40 Xaa41 Xaa42 Xaa43 Xaa44 Xaa45 Xaa46 Xaa47 Xaa48 Xaa49 Xaa50 Cys Xaa52 Xaa53 Xaa54 Cys Xaa56 Xaa57 Xaa58 (SEQ ID NO:1), wherein Xaa1, Xaa2, Xaa3, Xaa4, Xaa56, Xaa57 or Xaa58 are each individually an amino acid or absent;
Xaa6, Xaa7, Xaa8, Xaa9, Xaa20, Xaa24, Xaa25, Xaa26, Xaa27, Xaa28, Xaa29, Xaa41, Xaa42, Xaa44, Xaa46, Xaa47, Xaa48, Xaa49, Xaa50, Xaa52, Xaa53 and Xaa54 can be any amino acid; Xaa10 is an amino acid selected from the group consisting of: Asp and Glu; Xaa11 is an amino acid selected from the group consisting of: Asp, Gly, Ser, Val, Asn, Ile, Ala and Thr; Xaa13 is an amino acid selected from the group consisting of: Arg, His, Pro, Asn, Ser, Thr, Ala, Gly, Lys and Gln; Xaa15 is an amino acid selected from the group consisting of: Arg, Lys, Ala, Ser, Gly, Met, Asn and Gln; Xaa16 is an amino acid selected from the group consisting of: Ala, Gly, Ser, Asp and Asn; Xaa17 is an amino acid selected from the group consisting of: Ala, Asn, Ser, Ile, Gly, Val, Gln and Thr; Xaa18 is an amino acid selected from the group consisting of: His, Leu, Gln and Ala; Xaa19 is an amino acid selected from the group consisting of: Pro, Gln, Leu, Asn and Ile; Xaa21 is an amino acid selected from the group consisting of: Trp, Phe, Tyr, His and Ile; Xaa22 is an amino acid selected from the group consisting of: Tyr and Phe; Xaa23 is an amino acid selected from the group consisting of: Tyr and Phe; Xaa31 is an amino acid selected from the group consisting of: Glu, Asp, Gln, Asn, Ser, Ala, Val, Leu, Ile and Thr; Xaa32 is an amino acid selected from the group consisting of: Glu, Gln, Asp Asn, Pro, Thr, Leu, Ser, Ala, Gly and Val; Xaa34 is an amino acid selected from the group consisting of: Thr, Ile, Ser, Val, Ala, Asn, Gly and Leu; Xaa35 is an amino acid selected from the group consisting of: Tyr, Trp and Phe; Xaa39 is an amino acid selected from the group consisting of: Glu, Gly, Ala, Ser and Asp; Xaa40 is an amino acid selected from the group consisting of: Gly and Ala; Xaa43 is an amino acid selected from the group consisting of: Asn and Gly; Xaa45 is an amino acid selected from the group consisting of: Phe and Tyr; and wherein said polypeptide inhibits kallikrein.
- 7. The method of claim 6, wherein Xaa6 is Ala.
- 8. The method of claim 6, wherein Xaa7 is Phe.
- 9. The method of claim 6, wherein Xaa8 is Lys.
- 10. The method of claim 6, wherein Xaa9 is Ala.
- 11. The method of claim 6, wherein Xaa10 is Asp.
- 12. The method of claim 6, wherein Xaa11 is Asp.
- 13. The method of claim 6, wherein Xaa13 is Pro, Xaa15 is Arg, Xaa16 is Ala, Xaa17 is Ala, Xaa18 is His and Xaa19 is Pro.
- 14. The method of claim 6, wherein Xaa20 is Arg.
- 15. The method of claim 6, wherein Xaa24 is Asn.
- 16. The method of claim 6, wherein Xaa25 is Ile.
- 17. The method of claim 6, wherein Xaa26 is Phe.
- 18. The method of claim 6, wherein Xaa27 is Thr.
- 19. The method of claim 6, wherein Xaa28 is Arg.
- 20. The method of claim 6, wherein Xaa29 is Gln.
- 21. The method of claim 6, wherein Xaa31 is Glu.
- 22. The method of claim 6, wherein Xaa32 is Glu.
- 23. The method of claim 6, wherein Xaa34 is Ile.
- 24. The method of claim 6, wherein Xaa35 is Tyr.
- 25. The method of claim 6, wherein Xaa39 is Glu.
- 26. The method of claim 6, wherein Xaa41 is Asn.
- 27. The method of claim 6, wherein Xaa42 is Arg.
- 28. The method of claim 6, wherein Xaa44 is Arg.
- 29. The method of claim 6, wherein Xaa46 is Glu.
- 30. The method of claim 6, wherein Xaa47 is Ser.
- 31. The method of claim 6, wherein Xaa48 is Leu.
- 32. The method of claim 6, wherein Xaa49 is Glu.
- 33. The method of claim 6, wherein Xaa50 is Glu.
- 34. The method of claim 6, wherein the polypeptide comprises two or more amino acids selected from the group consisting of: Asp at Xaa10; Asp at Xaa11; Pro at Xaa13; Arg at Xaa15; Ala at Xaa16; Ala at Xaa17; His at Xaa18; Pro at Xaa19; Tip at Xaa21; Phe at Xaa22; Phe at Xaa23; Glu at Xaa31; Glu at Xaa32; Ile at Xaa34; Tyr at Xaa35; Glu at Xaa39; Gly at Xaa40; Asn at Xaa43; and Phe at Xaa45.
- 35. The method of claim 6, wherein the polypeptide comprises five or more amino acids selected from the group consisting of: Asp at Xaa10; Asp at Xaa11; Pro at Xaa13; Arg at Xaa15; Ala at Xaa16; Ala at Xaa17; His at Xaa18; Pro at Xaa19; Trp at Xaa21; Phe at Xaa22; Phe at Xaa23; Glu at Xaa31; Glu at Xaa32; Ile at Xaa34; Tyr at Xaa35; Glu at Xaa39; Gly at Xaa40; Asn at Xaa43; and Phe at Xaa45.
- 36. The method of claim 6, wherein the polypeptide comprises ten or more amino acids selected from the group consisting of: Asp at Xaa10; Asp at Xaa11; Pro at Xaa13; Arg at Xaa15; Ala at Xaa16; Ala at Xaa17; His at Xaa18; Pro at Xaa19; Trp at Xaa21; Phe at Xaa22; Phe at Xaa23; Glu at Xaa31; Glu at Xaa32; Ile at Xaa34; Tyr at Xaa35; Glu at Xaa39; Gly at Xaa40; Asn at Xaa43; and Phe at Xaa45.
- 37. The method of claim 6, wherein the polypeptide comprises fifteen or more amino acids selected from the group consisting of: Asp at Xaa10; Asp at Xaa11; Pro at Xaa13; Arg at Xaa15; Ala at Xaa16; Ala at Xaa17; His at Xaa18; Pro at Xaa19; Trp at Xaa21; Phe at Xaa22; Phe at Xaa23; Glu at Xaa31; Glu at Xaa32; Ile at Xaa34; Tyr at Xaa35; Glu at Xaa39; Gly at Xaa40; Asn at Xaa43; and Phe at Xaa45.
- 38. The method of claim 6, wherein Xaa3 is Ser.
- 39. The method of claim 6, wherein Xaa2 is His.
- 40. The method of claim 6, wherein Xaa1 is Met.
- 41. The method of claim 6, wherein Xaa56 is Thr.
- 42. The method of claim 6, wherein Xaa57 is Arg.
- 43. The method of claim 6, wherein Xaa58 is Asp.
- 44. The method according to claim 6, wherein the kallikrein inhibitor is a polypeptide comprising amino acids 3-60 of SEQ ID NO:2.
- 45. The method according to claim 6, wherein the kallikrein inhibitor is a polypeptide comprising SEQ ID NO:2.
- 46. The method of claim 6, wherein the organ or tissue is heart, lung, kidney, pancreas, liver, intestine, endothelial tissue, vascular tissue or skin.
- 47. A method for reducing reperfusion injury of an organ during surgery and/or following removal of the organ from a subject, comprising placing the organ in an organ storage and preservative solution, wherein the solution comprises a kallikrein inhibitor.
- 48. The method according to claim 47, wherein the kallikrein inhibitor is a polypeptide comprising SEQ ID NO:1, wherein
Xaa1, Xaa2, Xaa3, Xaa4, Xaa56, Xaa57 or Xaa58 are each individually an amino acid or absent; Xaa6, Xaa7, Xaa8, Xaa9, Xaa20, Xaa24, Xaa25, Xaa26, Xaa27, Xaa28, Xaa29, Xaa41, Xaa42, Xaa44, Xaa46, Xaa47, Xaa48, Xaa49, Xaa50, Xaa52, Xaa53 and Xaa54 can be any amino acid; Xaa10 is an amino acid selected from the group consisting of: Asp and Glu; Xaa11 is an amino acid selected from the group consisting of: Asp, Gly, Ser, Val, Asn, Ile, Ala and Thr; Xaa13 is an amino acid selected from the group consisting of: Arg, His, Pro, Asn, Ser, Thr, Ala, Gly, Lys and Gln; Xaa15 is an amino acid selected from the group consisting of: Arg, Lys, Ala, Ser, Gly, Met, Asn and Gln; Xaa16 is an amino acid selected from the group consisting of: Ala, Gly, Ser, Asp and Asn; Xaa17 is an amino acid selected from the group consisting of: Ala, Asn, Ser, Ile, Gly, Val, Gln and Thr; Xaa18 is an amino acid selected from the group consisting of: His, Leu, Gln and Ala; Xaa19 is an amino acid selected from the group consisting of: Pro, Gln, Leu, Asn and Ile; Xaa21 is an amino acid selected from the group consisting of: Trp, Phe, Tyr, His and Ile; Xaa22 is an amino acid selected from the group consisting of: Tyr and Phe; Xaa23 is an amino acid selected from the group consisting of: Tyr and Phe; Xaa31 is an amino acid selected from the group consisting of: Glu, Asp, Gln, Asn, Ser, Ala, Val, Leu, Ile and Thr; Xaa32 is an amino acid selected from the group consisting of: Glu, Gln, Asp Asn, Pro, Thr, Leu, Ser, Ala, Gly and Val; Xaa34 is an amino acid selected from the group consisting of: Thr, Ile, Ser, Val, Ala, Asn, Gly and Leu; Xaa35 is an amino acid selected from the group consisting of: Tyr, Trp and Phe; Xaa39 is an amino acid selected from the group consisting of: Glu, Gly, Ala, Ser and Asp; Xaa40 is an amino acid selected from the group consisting of: Gly and Ala; Xaa43 is an amino acid selected from the group consisting of: Asn and Gly; Xaa45 is an amino acid selected from the group consisting of: Phe and Tyr.
- 49. The method according to claim 47, wherein the kallikrein inhibitor is a polypeptide comprising amino acids 3-60 of SEQ ID NO:2.
- 50. The method according to claim 47, wherein the kallikrein inhibitor is a polypeptide comprising SEQ ID NO:2.
- 51. The method of claim 47, wherein the organ or tissue is heart, lung, kidney, pancreas, liver, intestine, endothelial tissue, vascular tissue or skin.
- 52. A composition for preserving and/or storing an organ comprising a physiologically acceptable ex vivo organ preservation solution containing a polypeptide comprising the amino acid sequence: Xaa1 Xaa2 Xaa3 Xaa4 Cys Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Gly Xaa13 Cys Xaa15 Xaa16 Xaa17 Xaa18 Xaa19 Xaa20 Xaa21 Xaa22 Xaa23 Xaa24 Xaa25 Xaa26 Xaa27 Xaa28 Xaa29 Cys Xaa31 Xaa32 Phe Xaa34 Xaa35 Gly Gly Cys Xaa39 Xaa40 Xaa41 Xaa42 Xaa43 Xaa44 Xaa45 Xaa46 Xaa47 Xaa48 Xaa49 Xaa50 Cys Xaa52 Xaa53 Xaa54 Cys Xaa56 Xaa57 Xaa58 (SEQ ID NO:1), wherein
Xaa1, Xaa2, Xaa3, Xaa4, Xaa56, Xaa57 or Xaa58 are each individually an amino acid or is absent; Xaa6, Xaa7, Xaa8, Xaa9, Xaa20, Xaa24, Xaa25, Xaa26, Xaa27, Xaa28, Xaa29, Xaa41, Xaa42, Xaa44, Xaa46, Xaa47, Xaa48, Xaa49, Xaa50, Xaa52, Xaa53 and Xaa54 can be any amino acid; Xaa10 is an amino acid selected from the group consisting of: Asp and Glu; Xaa11 is an amino acid selected from the group consisting of: Asp, Gly, Ser, Val, Asn, Ile, Ala and Thr; Xaa13 is an amino acid selected from the group consisting of: Arg, His, Pro, Asn, Ser, Thr, Ala, Gly, Lys and Gln; Xaa15 is an amino acid selected from the group consisting of: Arg, Lys, Ala, Ser, Gly, Met, Asn and Gln; Xaa16 is an amino acid selected from the group consisting of: Ala, Gly, Ser, Asp and Asn; Xaa17 is an amino acid selected from the group consisting of: Ala, Asn, Ser, Ile, Gly, Val, Gln and Thr; Xaa18 is an amino acid selected from the group consisting of: His, Leu, Gln and Ala; Xaa19 is an amino acid selected from the group consisting of: Pro, Gln, Leu, Asn and Ile; Xaa21 is an amino acid selected from the group consisting of: Trp, Phe, Tyr, His and Ile; Xaa22 is an amino acid selected from the group consisting of: Tyr and Phe; Xaa23 is an amino acid selected from the group consisting of: Tyr and Phe; Xaa31 is an amino acid selected from the group consisting of: Glu, Asp, Gln, Asn, Ser, Ala, Val, Leu, Ile and Thr; Xaa32 is an amino acid selected from the group consisting of: Glu, Gln, Asp Asn, Pro, Thr, Leu, Ser, Ala, Gly and Val; Xaa34 is an amino acid selected from the group consisting of: Thr, Ile, Ser, Val, Ala, Asn, Gly and Leu; Xaa35 is an amino acid selected from the group consisting of: Tyr, Trp and Phe; Xaa39 is an amino acid selected from the group consisting of: Glu, Gly, Ala, Ser and Asp; Xaa40 is an amino acid selected from the group consisting of: Gly and Ala; Xaa43 is an amino acid selected from the group consisting of: Asn and Gly; Xaa45 is an amino acid selected from the group consisting of: Phe and Tyr; and wherein said polypeptide inhibits kallikrein.
- 53. The composition of claim 52, wherein Xaa6 is Ala.
- 54. The composition of claim 52, wherein Xaa7 is Phe.
- 55. The composition of claim 52, wherein Xaa8 is Lys.
- 56. The composition of claim 52, wherein Xaa9 is Ala.
- 57. The composition of claim 52, wherein Xaa10 is Asp.
- 58. The composition of claim 52, wherein Xaa11 is Asp.
- 59. The composition of claim 52, wherein Xaa13 is Pro, Xaa15 is Arg, Xaa16 is Ala, Xaa17 is Ala, Xaa18 is His and Xaa19 is Pro.
- 60. The composition of claim 52, wherein Xaa20 is Arg.
- 61. The composition of claim 52, wherein Xaa24 is Asn.
- 62. The composition of claim 52, wherein Xaa25 is Ile.
- 63. The composition of claim 52, wherein Xaa26 is Phe.
- 64. The composition of claim 52, wherein Xaa27 is Thr.
- 65. The composition of claim 52, wherein Xaa28 is Arg.
- 66. The composition of claim 52, wherein Xaa29 is Gln.
- 67. The composition of claim 52, wherein Xaa31 is Glu.
- 68. The composition of claim 52, wherein Xaa32 is Glu.
- 69. The composition of claim 52, wherein Xaa34 is Ile.
- 70. The composition of claim 52, wherein Xaa35 is Tyr.
- 71. The composition of claim 52, wherein Xaa39 is Glu.
- 72. The composition of claim 52, wherein Xaa41 is Asn.
- 73. The composition of claim 52, wherein Xaa42 is Arg.
- 74. The composition of claim 52, wherein Xaa44 is Arg.
- 75. The composition of claim 52, wherein Xaa46 is Glu.
- 76. The composition of claim 52, wherein Xaa47 is Ser.
- 77. The composition of claim 52, wherein Xaa48 is Leu.
- 78. The composition of claim 52, wherein Xaa49 is Glu.
- 79. The composition of claim 52, wherein Xaa50 is Glu.
- 80. The composition of claim 52, wherein the polypeptide comprises two or more amino acids selected from the group consisting of: Asp at Xaa10; Asp at Xaa11; Pro at Xaa13; Arg at Xaa15; Ala at Xaa16; Ala at Xaa17; His at Xaa18; Pro at Xaa19; Trp at Xaa21; Phe at Xaa22; Phe at Xaa23; Glu at Xaa31; Glu at Xaa32; Ile at Xaa34; Tyr at Xaa35; Glu at Xaa39; Gly at Xaa40; Asn at Xaa43; and Phe at Xaa45.
- 81. The composition of claim 52, wherein the polypeptide comprises five or more amino acids selected from the group consisting of: Asp at Xaa10; Asp at Xaa11; Pro at Xaa13; Arg at Xaa15; Ala at Xaa16; Ala at Xaa17; His at Xaa18; Pro at Xaa19; Trp at Xaa21; Phe at Xaa22; Phe at Xaa23; Glu at Xaa31; Glu at Xaa32; Ile at Xaa34; Tyr at Xaa35; Glu at Xaa39; Gly at Xaa40; Asn at Xaa43; and Phe at Xaa45.
- 82. The composition of claim 52, wherein the polypeptide comprises ten or more amino acids selected from the group consisting of: Asp at Xaa10; Asp at Xaa11; Pro at Xaa13; Arg at Xaa15; Ala at Xaa16; Ala at Xaa17; His at Xaa18; Pro at Xaa19; Trp at Xaa21; Phe at Xaa22; Phe at Xaa23; Glu at Xaa31; Glu at Xaa32; Ile at Xaa34; Tyr at Xaa35; Glu at Xaa39; Gly at Xaa40; Asn at Xaa43; and Phe at Xaa45.
- 83. The composition of claim 52, wherein the polypeptide comprises fifteen or more amino acids selected from the group consisting of: Asp at Xaa10; Asp at Xaa11; Pro at Xaa13; Arg at Xaa15; Ala at Xaa16; Ala at Xaa17; His at Xaa18; Pro at Xaa19; Trp at Xaa21; Phe at Xaa22; Phe at Xaa23; Glu at Xaa31; Glu at Xaa32; Ile at Xaa34; Tyr at Xaa35; Glu at Xaa39; Gly at Xaa40; Asn at Xaa43; and Phe at Xaa45.
- 84. The composition of claim 52, wherein Xaa3 is Ser.
- 85. The composition of claim 52, wherein Xaa2 is His.
- 86. The composition of claim 52, wherein Xaa1 is Met.
- 87. The composition of claim 52, wherein Xaa56 is Thr.
- 88. The composition of claim 52, wherein Xaa57 is Arg.
- 89. The composition of claim 52, wherein Xaa58 is Asp.
- 90. The composition according to claim 52, wherein the polypeptide comprises SEQ ID NO:2.
- 91. A method for preserving an organ or tissue comprising contacting the organ or tissue with a physiologically acceptable ex vivo organ preservation solution containing a kallikrein binding polypeptide.
- 92. The method according to claim 91, wherein the kalilkrein binding polypeptide comprises SEQ ID NO:2.
- 93. The method of claim 91, wherein the organ or tissue is heart, lung, kidney, pancreas, liver, intestine, endothelial tissue, vascular tissue or skin.
- 94. The method of claim 91, wherein the kallikrein binding polypeptide comprises a Kunitz domain.
- 95. The method of claim 94, wherein the Kunitz domain comprises a cysteine at each of positions 5 and 55; 14 and 38; and 30 and 51, and further comprises:
amino acid number 13 selected from His and Pro; amino acid number 16 selected from Ala and Gly; amino acid number 17 selected from Ala, Asn, and Ser; amino acid number 18 selected from His and Leu; and amino acid number 19 selected from Gln, Leu, and Pro (SEQ ID NO:23), wherein the amino acid numbering corresponds to the amino acid positions of the Kunitz domain of bovine pancreatic trypsin inhibitor (BPTI).
- 96. The method of claim 94, wherein the Kunitz domain comprises a cysteine at each of positions 5 and 55; 14 and 38; and 30 and 51, and further comprises:
amino acid number 13 selected from His and Pro; amino acid number 15 selected from Lys and Arg; amino acid number 16 selected from Ala and Gly; amino acid number 17 selected from Ala, Asn, and Ser; amino acid number 18 selected from His and Leu; and amino acid number 19 selected from Gln, Leu, and Pro, amino acid number 31 is Glu; amino acid number 32 selected from Glu and Gln; amino acid number 34 selected from Ser, Thr, and Ile; and amino acid number 39 selected from Gly, Glu, and Ala (SEQ ID NO:24), wherein the amino acid numbering corresponds to the amino acid positions of the Kunitz domain of bovine pancreatic trypsin inhibitor (BPTI).
- 97. A method according to claim 94, wherein the Kunitz domain is selected from the group consisting of
KKII/3 #1 (SEQ ID NO:24) KKII/3 #2 (SEQ ID NO:25) KKII/3 #3 (SEQ ID NO:26) KKII/3 #4 (SEQ ID NO:27) KKII/3 #5 (SEQ ID NO:28) KKII/3 #6 (SEQ ID NO:29) KKII/3 #7 (SEQ ID NO:30) KKII/3 #8 (SEQ ID NO:31) KKII/3 #9 (SEQ ID NO:32) and KKII/3 #10 (SEQ ID NO:33).
RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application No. 60/407,004, filed Aug. 28, 2002.
Provisional Applications (1)
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Number |
Date |
Country |
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60407004 |
Aug 2002 |
US |