Potent and selective DHFR inhibitors for treating Cryptosporidiosis

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DESCRIPTION (provided by applicant): This STTR application requests funds to support the transfer of specific biophysical and synthetic expertise from the Anderson and Wright Groups at the University of Connecticut to investigators at Promiliad Biopharma in a joint effort to develop best-in-class therapeutic agents for the treatment of cryptosporidiosis. This water-borne protozoan, Cryptosporidium spp. represents an emerging infectious disease and has been placed on NIAID's class B list of potential biodefense hazards. These efforts will focus on inhibitors of dihydrofolate reductase (DHFR), a key enzyme involved in the production of deoxythymidine monophospate and critical for the survival of the parasitic organism. Although inhibition of this enzyme has proven a successful strategy to combat malaria, bacterial infections and toxoplasmosis, there has been no success in treating cryptosporidiosis with DHFR inhibitors. The need for the development of such agents is underscored by the absence of any effective agents against Cryptosporidium. The Anderson group has recently solved the crystal structure of DHFR-TS derived from Cryptosporidium and has identified several features of the active site that can be exploited to design potent and selective inhibitors of Cryptosporidium DHFR. In collaboration with the Wright group and Promiliad Biopharma, a series of novel classes of inhibitors have been designed to display enhanced levels of potency and selectivity. Through this STTR initiative we will create moderately sized libraries of novel inhibitors though parallel synthesis, screen these libraries for potent and selective inhibitors of C. hominis DHFR using in vitro enzyme and cell culture assays. We expect to discover several novel inhibitors that will provide the foundation for Phase II research for the development of new therapeutics.