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Computationally Designed Heparan Sulfates and Pathophysiology

计算设计的硫酸乙酰肝素和病理生理学

基本信息

批准号：
8516576
负责人：
Umesh Ramanlal Desai
金额：
$ 31.59万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8516576
关键词：
Address Affect Affinity Agonist Animal Model Animal Testing Anticoagulants Anticoagulation Area Atomic Force Microscopy Belief System Binding Biochemical Biological Process Biology Biopolymers Chemistry Clinical Coagulation Process Development Disease Enzymes Escherichia coli Factor IXa Factor Xa Fibroblast Growth Factor 1 Functional disorder GAG Gene Glycoproteins Growth Growth Factor HIV Envelope Protein gp120 HIV-1 Heparin Heparin Cofactor II Heparitin Sulfate IL8 gene Immune response In Vitro Individual Inflammation Instruction Investigation Kinetics Knowledge Laboratories Legal patent Libraries Low-Molecular-Weight Heparin Modeling Molecular Morphology Nature Paper Pathologic Processes Peptide Hydrolases Pharmacologic Substance Physiological Processes Plasma Play Positioning Attribute Preparation Property Proteins Research Role Serpins Simplexvirus Specificity Structure Structure-Activity Relationship System Technology Testing Thermodynamics Thrombin Thrombosis Time Viral Virtual Library Work Xenograft procedure angiogenesis base beta-Thromboglobulin capsular polysaccharide K5 cell envelope chemokine combinatorial computer studies design evaluation/testing experience fondaparinux heparin cofactor in vivo inhibitor/antagonist pathogen receptor screening sulfotransferase

项目摘要

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. RELEVANCE (See instructions): 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.

天然生物聚合物肝素和硫酸肝素在大量的生物活性物质中起着至关重要的作用