NEW CHEMICAL ENTITIES AND UNIQUE TARGETS FOR HCMV

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The overall goal of the proposed research is to design, synthesize new heterocyclic compounds, nucleoside analogs, and prodrugs thereof as potential drugs for the treatment of herpesvirus infections, particularly those caused by human cytomegalovirus (HCMV). Compound design will be based upon our recent discoveries of new lead compounds and on evidence for new antiviral targets. The latter studies will be based upon preliminary data which show a unique mode of action for new compounds. The overall approach will involve interactions among two synthesis projects, in vitro biological evaluation, virological and biochemical studies, and in vivo evaluation plus initial toxicology and pharmacokinetics. The primary rationale is to design and synthesize compounds that will be potent and specific inhibitors of HCMV replication. The detailed specific aims by which these objectives will be accomplished are described in the specific aims section for each of the research projects. The aims can be summarized as follows: 1) Research Projects 1 and 2 will design and synthesize new compounds and prodrugs as potential agents for HCMV infections. The synthetic efforts will be guided by feedback from the biological components of the Program. 2) Research Project 3 will provide initial evaluation of new compounds for activity against HCMV (plaque reduction and yield reduction) and herpes simplex virus type 1 (HSV-1) as well as for cytotoxicity in uninfected cells. This project also will be responsible for investigating the mode of new and existing compounds to better understand their action and also to identify new viral drug targets. Studies will include in vitro drug metabolism, inhibition of certain target enzymes or biological processes, molecular biology, and viral genetics. 4) The Scientific Core will provide more extensive in vitro evaluation of new compounds against other human herpesviruses and animal herpesviruses, in vivo testing of the most promising new compounds, plus initial toxicology and pharmacokinetic evaluation. In these ways, we shall provide a comprehensive program for the critical initial phases of drug discovery and development of new therapies for an important AIDS-associated opportunistic infection.