This project attempts to develop novel molecules as allosteric anticoagulants of coagulation proteases, especially thrombin and factor XIa. The hypothesis is that targeting these proteases through allosteric disruption of their catalytic triad results in controlled inhibition, which is likely to not suffer from bleeding consequences. All current anticoagulants including the heparins, warfarin, dabigatran and rivaroxaban suffer from enhanced risk of bleeding. The past grant period resulted in two groups of highly promising inhibitors of thrombin and factor XIa. The thrombin inhibitors displayed regulatory features (maximal inhibition in the region of 50 - 75%), which is likely to maintain hemostasis, especially under prophylactic application. Likewise, factor XIa inhibitors are likely to be devoid of bleeding because of the inherent mechanism of action of factor XIa, which is its action on the thrombotic process while leaving hemostatic process intact. In addition, the allosteric inhibitors are predicted to possess a higher specificity of action, which would reduce off target effects. Thus, the two groups of inhibitors are predicted to lead to a safer anticoagulant therapy. In fact, we have found that one of our designed molecules showed marked anticoagulant activities in FeCl3-induced thrombosis in the carotid artery mouse model without affecting bleeding time supporting the hypothesis. In this grant period, we intend to I) design more potent, selective regulators of human thrombin; II) develop more potent, selective inhibitors of human factor XIa and III) perform pre-clinical studies on promising advanced thrombin regulators and FXIa inhibitors.

Public Health Relevance

Thrombosis is a leading cause of morbidity and mortality associated with arterial and venous disorders. Nearly 1 in 3 individuals in the US suffer from thrombotic disorders. The current anticoagulants including warfarin, heparin, dabigatran and rivaroxaban suffer from significant risk of bleeding and other agent-specific problems including unpredictable pharmacokinetics and drug-drug interactions. The goal of this project is to develop safer anticoagulant drug based on our initials results with allosteric inhibition of thrombin and factor XIa.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090586-07
Application #
9310378
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Warren, Ronald Q
Project Start
2009-07-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Boothello, Rio S; Patel, Nirmita J; Sharon, Chetna et al. (2018) A Unique Non-Saccharide Mimetic of Heparin Hexasaccharide Inhibits Colon Cancer Stem Cells via p38 MAP Kinase Activation. Mol Cancer Ther :
Abdel Aziz, May H; Desai, Umesh R (2018) Novel heparin mimetics reveal cooperativity between exosite 2 and sodium-binding site of thrombin. Thromb Res 165:61-67
Gangji, Rahaman Navaz; Sankaranarayanan, Nehru Viji; Elste, James et al. (2018) Inhibition of Herpes Simplex Virus-1 Entry into Human Cells by Nonsaccharide Glycosaminoglycan Mimetics. ACS Med Chem Lett 9:797-802
Sankaranarayanan, Nehru Viji; Nagarajan, Balaji; Desai, Umesh R (2018) So you think computational approaches to understanding glycosaminoglycan-protein interactions are too dry and too rigid? Think again! Curr Opin Struct Biol 50:91-100
Afosah, Daniel K; Verespy 3rd, Stephen; Al-Horani, Rami A et al. (2018) A small group of sulfated benzofurans induces steady-state submaximal inhibition of thrombin. Bioorg Med Chem Lett 28:1101-1105
Patel, Nirmita J; Sharon, Chetna; Baranwal, Somesh et al. (2016) Heparan sulfate hexasaccharide selectively inhibits cancer stem cells self-renewal by activating p38 MAP kinase. Oncotarget 7:84608-84622
Mehta, A Y; Mohammed, B M; Martin, E J et al. (2016) Allosterism-based simultaneous, dual anticoagulant and antiplatelet action: allosteric inhibitor targeting the glycoprotein Ib?-binding and heparin-binding site of thrombin. J Thromb Haemost 14:828-38
Mosier, Philip D; Chiang, Meng-Jung; Lin, Zhengshi et al. (2016) Broad Spectrum Anti-Influenza Agents by Inhibiting Self-Association of Matrix Protein 1. Sci Rep 6:32340
Verespy 3rd, Stephen; Mehta, Akul Y; Afosah, Daniel et al. (2016) Allosteric Partial Inhibition of Monomeric Proteases. Sulfated Coumarins Induce Regulation, not just Inhibition, of Thrombin. Sci Rep 6:24043
Al-Horani, Rami A; Desai, Umesh R (2016) Factor XIa inhibitors: A review of the patent literature. Expert Opin Ther Pat 26:323-45

Showing the most recent 10 out of 55 publications