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.
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.
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