The purpose of this study is to provide a survey of spatial requirements of cell-surface carbohydrates antigens in order to identify soluble receptor analogs which could competitively inhibit pathogenic bacteria/viral attachment. Three targets are addressed: 1) Influenza virus - inhibition of viral attachment to sialic acid residues by designing inhibitors with C2 or C3 symmetry which are capable of multidentate (intra- or intermolecular) binding to the viral hemagglutinin coat proteins. 2) Helicobacter pylori - inhibition of bacterial attachment to human gastric mucosa mediated by the fucose-containing Lewis (b) blood group antigen. This bacteria is the causative agent in chronic active gastritis, gastric and duodenal ulcers, and gastric adenocarcinoma, one of the most common forms of cancer in humans. The tetrasaccharide Lewis (b), as well as a Lewis (b)-albumin conjugate (32 copies of Lewis (b) on surface of albumin have recently been shown in vitro to be inhibitors for adhesion of H. pylori to human gastric surface mucosal cells. The synthesis of C- analogs of Lewis (b) (O-analogs are incompatible with the gastric environment) including a combinatorial library of C-oligosaccharides will be targeted. 3) Actinomyces viscosus and Actinomyces naeslundii - Inhibition of attachment to oral endothelial cells mediated by a beta-galactose residue. A systematic clustering survey using readily available C-beta-galactose analogs is designed to map out the as yet unknown receptor geometry using an Ugi four-component condensation as a highly efficient strategy for the generation of high-density oligosaccharide clusters. The synthetic efforts in the proposal are divided into two sections. The first involves the synthesis of the carbon-linked analogs of the three relevant cell surface antigens: a) C-N-acetylneuraminic acid, b) C-and/or O-linked Lewis (b) tetrasaccharide derivatives, and, c) C-galactose. The second section involves the synthesis of appropriate scaffolding for the first systematic study of polydentate inhibitors where antigen analogs are positioned over large distances (up to 100 A apart). This involves the incorporation of C-acetylenic oligosaccharides (already synthesized by us) into symmetry-related oligomers and dendromers. This proposal outlines a plan for synthesizing large libraries of unique soluble receptor analogs for each target and the methods for assaying these inhibitors. Our intent is to systematically survey spatial relationships of potential ligands on oligosaccharide scaffoldings as an empirical approach to the design of inhibitors. The successful accomplishment of these goals will provide a research tool for the systematic study of molecular interactions involving macromolecular structures. In addition, it will provide some insight into the design, synthesis, and conformational analysis of carbohydrate oligomers capable of interfering in binding processes involving surface antigens.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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