Antithrombotic compounds, methods and uses thereof
Provided herein are polymers and methods for their use in binding a phosphate containing biological macromolecules. Specifically, the methods and uses provided herein may be used to inhibit thrombin binding to polyphosphate or as an antithrombotic agent for the treatment of stroke, acute coronary syndrome, pulmonary embolism, atrial fibrillation, venous and arterial thromboembolism, disseminated intravascular coagulation (DIC), deepvein thrombosis (DVT), peripheral artery disease, trauma-induced coagulopathy, extracorporeal circulation, cancer-associated thrombosis, sepsis, septic shock, Systemic Inflammatory Response Syndrome (SIRS), or inflammation.
1. A method of binding a phosphate containing biological macromolecule, the method comprising adding a Universal Heparin Reversal Agent (UHRA) polymer to a phosphate containing biological macromolecule sample, wherein the UHRA polymer comprises: a) a dendritic polyglycerol core having 2-33 randomly distributed tetra-amine groups, wherein the tetra-amines have the following structure
and wherein the molecular weight of the polymer in kDa per tetra-amine group does not exceed 4.5; and (b) an outer shell, wherein the outer shell is a hydrophilic polymeric system,
wherein the hydrophilic polymeric system is selected from the group consisting of polyether, polyalcohol, polyglycerol, linear polyglycerol, oligosaccharide, poly(Nisopropylacrylamide (PNIPAM), polyacrylamide (PAM), poly(2-oxazoline), poly(ethylene glycol), methoxy(polyethylene glycol), poly(ethylene oxide), poly(vinyl alcohol) (PVA), and poly(vinylpyrrolidone) (PVP), and combinations thereof, and
wherein the UHRA polymer is selected from the group consisting of UHRA-1, UHRA-2, UHRA-5, UHRA-6, UHRA-7, UHRA-8, UHRA-9, UHRA-10, UHRA-11, UHRA-13, UHRA-14 and UHRA-15.
2. The method of claim 1 , wherein the outer shell is selected from one or more of:
wherein n is 0-100, x is 0-100 and y is 0-100;
n is an integer between 1 and 20, x is an integer between 1 and 20 and y is an integer between 1 and 20;
n is an integer between 3 and 10, x is an integer between 3 and 10 and y is an integer between 3 and 10;
n is an integer between 4 and 9, x is an integer between 4 and 9 and y is an integer between 4 and 9; or
n is an integer between 5 and 8, x is an integer between 5 and 8 and y is an integer between 5 and 8.
3. The method of claim 1 , wherein the binding of the phosphate containing biological macromolecule results in neutralization.
4. The method of claim 1 , wherein the phosphate containing biological macromolecule is polyphosphate or a nucleic acid.
5. The method of claim 1 , wherein the phosphate containing biological macromolecule is polyphosphate.
6. The method of claim 4 , wherein the binding to polyphosphate disrupts the interaction between thrombin and polyphosphate.
7. The method of claim 1 , wherein the polyglycerol core has between 7-24 randomly distributed tetra-amine groups,
or wherein the polyglycerol core has between 11-24 randomly distributed tetra-amine groups.
8. The method of claim 1 , wherein the molecular weight of the UHRA polymer in kDa per tetra-amine group is between 0.9 and 4.5,
or wherein the molecular weight of the UHRA polymer in kDa per tetra-amine group does not exceed 3.6.
9. The method of claim 1 , wherein the UHRA polymer has an IC 50 (nM) for inhibition of thrombin binding to polyphosphate is equal to or less than 50 nM.
10. The method of claim 1 , wherein the polyglycerol core has a degree of branching in the range of about 0.05 to about 0.95,
or in the range of about 0.40 to about 0.65.
11. The method of claim 1 , wherein the UHRA polymer is immobilized on a support.
12. The method claim 1 , wherein the shell polymer is between about 10 to about 90 wt %.
13. The method of claim 1 , wherein the dendritic polyglycerol core has 5-33 randomly distributed tetra-amine groups.
14. The method of claim 1 , wherein the dendritic polyglycerol core has 2-23 randomly distributed tetra-amine groups.
15. The method of claim 1 , wherein the dendritic polyglycerol core has 7-16 randomly distributed tetra-amine groups.
16. The method of claim 1 , wherein the dendritic polyglycerol core has 8-16 randomly distributed tetra-amine groups.
17. The method of claim 2 , wherein the UHRA polymer is immobilized on a support.
18. The method of claim 7 , wherein the UHRA polymer is immobilized on a support.
19. The method of claim 8 , wherein the UHRA polymer is immobilized on a support.
20. The method of claim 12 , wherein the UHRA polymer is immobilized on a support.