Thrombotic disorders afflict a large number of people. Nearly 576,000 new cases of deep vein thrombosis and pulmonary embolism, two of the most common thrombotic conditions, are diagnosed every year in the US alone. Even more alarming is that thrombotic disorders are ~3-fold more likely in people with cancer. Anticoagulants, including heparins and coumarins, are the mainstay of treatment and prevention of thromboembolic disorders. Yet, the current anticoagulation therapy is beset with a significant number of adverse reactions including enhanced bleeding risk, immunological reaction, genetic variation in metabolism, food or drug interactions and liver toxicity. In addition, problems such as patient-to-patient response variability, narrow therapeutic index, inadequate duration of action, poor oral bioavailability, the need for frequent coagulation monitoring, and high cost to benefit ratio further complicate the treatment of thrombotic conditions. We reasoned that to reduce the problems associated with the current anticoagulation therapy, molecules radically different from all the current agents (heparins, warfarins, hirudins, and peptidomimetics) should be discovered. We have discovered that chemo-enzymatically synthesized lignins, represented by three sulfated dehydropolymer (DHP) molecules, named CDs, FDs and SDs, possess extremely interesting anticoagulant properties and a novel mechanism of action. 1) Sulfated DHPs (CDs, FDs and SDs) prolong prothrombin time at concentrations 2-6-fold below that of the clinically used LMWH enoxaparin, while in the activated partial thromboplastin time assay they required 2-6-fold higher concentration. 2) Whole blood clotting studies using thromboelastography and hemostasis analysis system reveal that our novel anticoagulants inhibit clotting with potency only 18-30-fold weaker than enoxaparin. 3) Mechanistically, the new molecules inhibit thrombin, factor Xa and factor XIa with IC50 values in the range of 10-240 nM. 4) In contrast, they inhibit factor IXa and factor VIIa with IC50 values 60-170-fold and >840-fold higher, respectively suggesting high selectivity for thrombin and factor Xa. 5) This potent inhibition arises primarily from direct inhibition of thrombin and factor Xa, although indirect inhibition mediated by antithrombin may also contribute. 6) Direct inhibition arises from an allosteric disruption of thrombin's catalytic apparatus (reduction in kCAT). 7) Competitive binding studies suggest that CDs interacts with exosite II of thrombin, a site not typically associated with inhibition. 8) A chemically synthesized CDs-based monomer inhibits thrombin and factor Xa with an IC50 of ~30

Public Health Relevance

Nearly 576000 new cases of deep vein thrombosis and pulmonary embolism, two of the most common thrombotic conditions, are diagnosed every year in the US alone. Thrombotic disorders are even more prevalent in people with cancer. The proposed research on novel dual direct inhibitors of thrombin and factor Xa aims to improve current anticoagulation therapy, which is beset with significant number of adverse reactions and limitations.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Hemostasis and Thrombosis Study Section (HT)
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Link, Rebecca P
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Virginia Commonwealth University
Schools of Pharmacy
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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

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