NEW INHIBITORS AND NEW TARGETS TO DEVELOP HCMV DRUGS

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The overall goal of the proposed research is to design, synthesize and evaluate new heterocyclic compounds with potential for the inhibition of HCMV infections. This will be a comprehensive approach involving interactions between the synthesis program, the in vitro biological evaluation program, the immunological program, the in vivo evaluation core component and the industrial collaborator. The primary rationale is to design and synthesize compounds that will be potent and specific inhibitors of HCMV infections. This specificity (selectivity) will be established by evaluating compounds against other viruses (e.g. HSV-I) and normal mammalian cells in addition to HCMV. These studies will provide feedback to the synthesis program and allow the synthetic efforts to remain focussed on those areas with a very high potential of providing compounds with inhibitory properties against HCMV infections. The detailed specific aims by which the above stated objectives will be accomplished are described in the specific sections for each of the laboratory research programs. These aims can be summarized as follows: 1) to establish a Central Operations Component to facilitate the interactions and communication between the research programs the industrial collaborator and the NIAID staff; 2) (Laboratory Research Program I) to design and synthesize new heterocyclic compounds as potential agents against HCMV infections. The synthetic efforts will be guided to a certain extend by feedback from the biological components of the NCDDG; 3) (Laboratory Research Program II) to evaluate new heterocyclic compounds for activity against HCMV (plaque reduction and titer reduction), activity against other viruses (e.g. HSV I, HSV II, etc.), cytotoxicity (HFF and KB cells) and to perform in vitro metabolism studies and inhibition studies of certain target enzymes or biological processes; 4) (Laboratory Research Program III) to study the immunologic parameters of compounds deemed to be active HCMV agents by Laboratory Research Program II's criteria; 5) (In vivo Core Component) this laboratory will perform in vivo evaluations on a limited number of compounds, the selection being made by a consensus of the Principal Investigator, Program Leaders and the NIAID liaison; 6) (Industrial Collaboration) to involve the industrial collaborator in discussions and decisions on the appropriate studies that will be needed for the further development of agents that are at the in vivo evaluation stage.