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)
Research Project (R01)
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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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Henry, Brian L; Desai, Umesh R (2014) Sulfated low molecular weight lignins, allosteric inhibitors of coagulation proteinases via the heparin binding site, significantly alter the active site of thrombin and factor xa compared to heparin. Thromb Res 134:1123-9
Mehta, Akul Y; Jin, Yingzi; Desai, Umesh R (2014) An update on recent patents on thrombin inhibitors (2010 - 2013). Expert Opin Ther Pat 24:47-67
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Mehta, Akul Y; Desai, Umesh R (2014) Substantial non-electrostatic forces are needed to induce allosteric disruption of thrombin's active site through exosite 2. Biochem Biophys Res Commun 452:813-6
Saluja, Bhawana; Li, Hua; Desai, Umesh R et al. (2014) Sulfated caffeic acid dehydropolymer attenuates elastase and cigarette smoke extract-induced emphysema in rats: sustained activity and a need of pulmonary delivery. Lung 192:481-92
Mehta, Akul Y; Thakkar, Jay N; Mohammed, Bassem M et al. (2014) Targeting the GPIb? binding site of thrombin to simultaneously induce dual anticoagulant and antiplatelet effects. J Med Chem 57:3030-9
Al-Horani, Rami A; Desai, Umesh R (2014) Designing allosteric inhibitors of factor XIa. Lessons from the interactions of sulfated pentagalloylglucopyranosides. J Med Chem 57:4805-18
Al-Horani, Rami A; Desai, Umesh R (2014) Recent advances on plasmin inhibitors for the treatment of fibrinolysis-related disorders. Med Res Rev 34:1168-216
Argade, Malaika D; Mehta, Akul Y; Sarkar, Aurijit et al. (2014) Allosteric inhibition of human factor XIa: discovery of monosulfated benzofurans as a class of promising inhibitors. J Med Chem 57:3559-69
Al-Horani, Rami A; Ponnusamy, Pooja; Mehta, Akul Y et al. (2013) Sulfated pentagalloylglucoside is a potent, allosteric, and selective inhibitor of factor XIa. J Med Chem 56:867-78

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