Heparin-like glycosaminoglycans (HLGAGs) are the most acid naturally occurring biopolymers. These complex polysaccharides, found in the extracellular matrix, play a key role in regulating the biological activity of several proteins in the coagulation cascade along with many other processes of biomedical importance including growth factor interactions, virus entry, and angiogenesis. The relationship between structure and activity of HLGAGs is still very poorly understood due to the complexity and heterogeneity of these polymers. It has become increasingly evidence that defined lengths and sequences of HLGAGs are responsible for binding to a particular protein and modulating its biological activity. Determining of structure-function relationships of HLGAGs creates an opportunity for the discovery of novel therapeutic interventions for a variety of disease states. The overall thrust of the proposed research is the development of a modular, general synthetic strategy for the preparation of heparin-like glycosaminoglycans and non-natural analogs in solution and on a solid support. The defined structures that will be synthesized as part of the overall program will be used as molecular tools to elucidate the substrate specificity of 3-0-sulfotransferases, which are responsible for creating the fine structure of heparin. An understanding of the substrate specificity of these and other biosynthetic enzymes may also lay the foundation for the development of a combined chemo-enzymatic approach to the synthesis of defined HLGAGs. The results of the proposed research are expected t provide the basis for structural, biochemical, and biophysical studies into the structure-function relationship of HLGAGs. The determination of specific sequences involved in receptor binding holds great promise for the development of molecular tools which will allow us to modulate processes underlying viral entry, angiogenesis, kidney diseases and diseases of the central nervous system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL064799-05
Application #
6793481
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Jacobs, Tom P
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
2003-07-01
Budget End
2004-04-30
Support Year
5
Fiscal Year
2003
Total Cost
$206,013
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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