Natural biopolymers heparin and heparan sulfate play critical roles in a large number of biological processes including coagulation, growth and morphology, angiogenesis, immune response, inflammation, and pathogen invasion. In fact, heparin and its derivatives, low molecular weight heparins and fondaparinux, are clinically used as anticoagulants in a number of thrombotic disorders. The fundamental basis for the use of heparin in these disorders is its high affinity and high specificity interaction with antlthrombin, a plasma glycoprotein and inhibitor of coagulation enzymes, especially thrombin, factor Xa and factor IXa. Despite the longstanding use of heparin, it continues to suffer from a number of problems. Better heparin-based anticoagulation therapy is critically needed, especially at a time when its heterogeneous nature can also give rise to problems associated with contaminations. Additionally, although heparin and heparan sulfate play important roles in other physiological and pathological processes, no clinical agent has as yet been devised. The major reason for this state is the phenomenal structural diversity of H/HS, which results in a) the difficulty of preparing HS preparations with defined structural composition and b) the difficulty of studying the interaction of a large number of HS structures with multiple proteins. Major advances are necessary in these two areas to decode H/HS structure - function relationships so as to enable the design of agonists and/or antagonists for modulation of biological processes. This Project 11 of the PEG addresses the fundamental difficulty of studying the interactions of all possible HS sequences with any protein (i.e., area b) above) through a unique technology developed in the laboratory of the PL called combinatorial virtual library screening (CVLS) technology. In combination with Projects I, III and IV, we propose 1) to decipher fundamental aspects of HS structure - function relationships in the coagulation and inflammation system, and 2) to test this enhanced understanding in in vivo animal models, especially for the coagulation system. Thus, we propose to 1) study the importance of specific and non- specific interactions of heparan sulfate with proteins using computational approaches and identify promising structures for in vitro and in vivo investigation;2) develop computationally designed HS structures as specific activators of heparin cofactor II;and 3) investigate the interaction of designed H/HS with coagulation proteins at a molecular level for development as new clinically useful anticoagulants.

Public Health Relevance

Thrombotic disorders affect 1 in 3 individuals in the US. The proposed research involves the computational design, biochemical evaluation and animal testing of heparan sulfates as modulators of thrombotic disorders.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
United States
Zip Code
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
Wood, Jeremy P; Baumann Kreuziger, Lisa M; Desai, Umesh R et al. (2016) Blocking inhibition of prothrombinase by tissue factor pathway inhibitor alpha: a procoagulant property of heparins. Br J Haematol 175:123-32
Holman, Holly A; Tran, Vy M; Kalita, Mausam et al. (2016) BODIPY-Conjugated Xyloside Primes Fluorescent Glycosaminoglycans in the Inner Ear of Opsanus tau. J Assoc Res Otolaryngol 17:525-540
Iwase, Hayato; Ekser, Burcin; Hara, Hidetaka et al. (2016) Thyroid hormone: relevance to xenotransplantation. Xenotransplantation 23:293-9
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
Sawant, Kirti V; Poluri, Krishna Mohan; Dutta, Amit K et al. (2016) Chemokine CXCL1 mediated neutrophil recruitment: Role of glycosaminoglycan interactions. Sci Rep 6:33123
Sepuru, Krishna Mohan; Rajarathnam, Krishna (2016) CXCL1/MGSA Is a Novel Glycosaminoglycan (GAG)-binding Chemokine: STRUCTURAL EVIDENCE FOR TWO DISTINCT NON-OVERLAPPING BINDING DOMAINS. J Biol Chem 291:4247-55
Mitsuhashi, Shuji; Feldbrügge, Linda; Csizmadia, Eva et al. (2016) Luminal Extracellular Vesicles (EVs) in Inflammatory Bowel Disease (IBD) Exhibit Proinflammatory Effects on Epithelial Cells and Macrophages. Inflamm Bowel Dis 22:1587-95
Sepuru, Krishna Mohan; Nagarajan, Balaji; Desai, Umesh R et al. (2016) Molecular Basis of Chemokine CXCL5-Glycosaminoglycan Interactions. J Biol Chem 291:20539-50
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 Ibα-binding and heparin-binding site of thrombin. J Thromb Haemost 14:828-38

Showing the most recent 10 out of 107 publications