Variants of antithrombin III
Disclosed are compositions and methods related to variant antithrombin III molecules.
1. A variant antithrombin III, comprising a substitution at position P3, wherein the substitution at P3 is an E, H, K, L, P, Q, R, W, or Y.
2. The variant ATIII of claim 1 , wherein the variant ATIII has a combined activity greater than or equal to plasma ATIII in a coupled assay.
3. The variant ATIII of claim 2 , wherein the ATIII retains base thrombin inhibition activity of at least 5%.
4. The variant ATIII of claim 2 , wherein the variant ATIII produce a predicted half life of thrombin at 60 minutes after a bolus administration to a subject that is greater than or equal to 0.9 the half life following a plasma ATIII administration.
5. The variant antithrombin III of claim 2 , wherein the variant antithrombin III has an increased protease resistance greater than or equal to the protease resistance of plasma ATIII.
6. The variant antithrombin III of claim 2 , wherein the variant antithrombin III has an increased human neutrophil elastase resistance greater than or equal to the protease resistance of plasma ATIII.
7. The variant antithrombin III of claim 2 , wherein the variant antithrombin III has an increased cathepsin G resistance greater than or equal to the protease resistance of plasma ATIII.
8. The variant ATIII of claim 1 , wherein the variant ATIII retains increased protease resistance and retains observable anti-thrombin activity.
9. The variant ATIII of claim 1 , wherein the variant ATIII retains increased protease resistance and retains observable anti factor fXa activity.
10. A method of inhibiting septic disseminated intravascular coagulation in a subject comprising administrating an ATIII variant of claim 1 to a subject having septic disseminated intravascular coagulation, wherein the ATIII variants inhibit thrombin, thereby inhibiting septic disseminated intravascular coagulation in the subject.
11. A method of reducing sepsis in a subject, comprising administering an ATIII variant of claim 1 to a subject having sepsis, thereby reducing sepsis in the subject.
12. A method of inhibiting sepsis induced shock in a subject comprising administering an ATIII variant of claim 1 to a subject, thereby reducing sepsis induced shock in the subject.
13. A method of making the variant ATIII of claim 1 , comprising linking in an operative way a nucleic acid molecule encoding a protein set forth in SEQ ID NO:77 wherein the nucleic acid sequence comprises a sequence that hybridizes under stringent hybridization conditions to a sequence set forth SEQ ID NO:79, or a degenerate variant thereof, and a sequence controlling the expression of the nucleic acid.
14. A cell comprising the variant ATIII of claim 1 .
15. A cell produced by the process of transforming the cell with any of the disclosed nucleic acids of claim 13 .
16. A cell produced by the process of administering the variant ATIII of claim 1 .