The overall goal of this research project is to develop new types of agents for the treatment of HIV infections in humans. The general approach that we have selected is to interfere with the biosynthesis of glycoproteins, specifically gp120. We have chosen to inhibit certain enzymes involved in the oligosaccharide processing pathway of this glycoprotein. Glycoprotein gp120 has been shown to have mainly oligosaccharides of the complex type (biantennary) and high-mannose-type. Our initial target enzymes are in the pathways leading to the complex-type species of oligosaccharides.
The specific aims of this proposal are: 1. To design inhibitors of the following enzymes involved in the processing of linked oligosaccharides: a. alpha-Mannosidases I and II. b. N-Acetyilglucosaminyltransferases I and II. c. Galactosyltransferase. 2. To develop synthetic routes for the preparation of these inhibitors. 3. To evaluate the biologic activity of the new agents against HIV in cell culture. 4. To further evaluate promising compounds for their effects on the glycosylation pathway. 5. To assess potential toxicity of promising compounds. 6. To evaluate promising compounds in combination with other useful agents such as AZT against HIV in cell culture. Promising combinations would be assessed for potential toxicity. The types of compounds that we will be making are oligosaccharides, oligosaccharide analogs, and O- glycosylnucleosides. Standard organic synthetic chemistry will be used to prepared the various target compounds.
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