DRUG DISCOVERY FOR MICROSPORIDIAL INFECTIONS

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The susceptibility of AIDS patients to opportunistic infections is the distinguishing feature of AIDS and is responsible for its morbidity and mortality. Thus, ubiquitous organisms that are ordinarily benign become debilitating pathogens in the immunosuppressed individual. Among the species that have become especially problematic in AIDS patients are the unique protozoal microsporidia, obligate intracellular parasites that are now recognized as common causes of a variety of severe, chronic conditions. Unfortunately, despite the prevalence of microsporidial infections, there are no proven effective drugs available to combat these organisms or alleviate the associated symptoms. The overall goal of this Drug Discovery Group is the development of novel, effective agents that will be useful for the treatment of microsporidial disease. To help achieve this objective, the specific goal of this project is the design and synthesis of compounds that will selectively inhibit the growth and reproduction of microsporidia, with minimal host toxicity. Based on knowledge of the unusual life cycle of these organisms, and in particular, on biochemical information about the polar filament structure that underlies both the reproductive and infectious process, we propose a structure- and mechanism-based program to develop agents that will compromise this critical aspect of microsporidial metabolism. Specifically, we propose several series of selective tubulin binding ligands, since tubulin is vital to proper polar tube function and spore germination. These 1-deazapteridine analogs and related compounds are designed for reduced affinity for mammalian tubulin. The activity of our lead compounds validates this approach.