Synthesis and Applications of Biologically Active Carbohydrate Derivatives and Related Compounds

This proposal contains three separate sections. The first section proposes improvement of the anti-adhesion strategy against urinary tract infections (UTI), the second most diagnosed disease. Anti-adhesion drugs interfere with the binding of bacterial proteins to carbohydrates on tissue surfaces and thereby prevent bacterial colonization. Persistant UTI are initiated by binding of a protein, FimH, at the end of threadlike projections from the surfaces of certain strains of E. coli, to mannose attached to one of the proteins, uroplakin Ia, at the surface of the urinary tract. Binding changes the shape of the molecules making up the surface that allows bacterial entry and colonization. The proposal is to synthesize compounds that match what is known about the structures of the best binding mannose derivatives, then attach as many as possible to polyester dendrimers or to dendritic nanoparticles or to dendritic polymers, so as to bind as many as possible of the 200-500 pili on each bacterium, to eliminate the shielded bacterial colonies. A second section is to develop a vaccine against Lyme disease, a disease that is expanding northward around the world. Initially, improved syntheses of the two known small molecule antigens of Lyme disease would be developed. Then, methods for attachment of these compounds to polyester dendrimers would be sought that retained their antigenicity. The antigen-covered polyester dendrimers would be tested as vaccines. It is hoped that dendrimers covered with both antigens would produce vaccines that are both potent and active against all strains of the bacteria causing Lyme disease. In connection with the above areas, we have a long-standing interest in methods for the regioselective substitution of carbohydrates, needed to make biologically active molecules. Tin-containing compounds act as synthetic intermediates that give regioselective substitution. The third section proposes to investigate these reactions by both experimental and computational means and to improve the reaction by making it catalytic in tin. It also proposes to investigate alternative reactions.