The overall objective of Research Project 3 is two-fold: (i) to identify by in vitro evaluation new compounds which have the potential to become useful antiviral drugs and (ii) to investigate how promising compounds act at the cellular, molecular and biochemical level to discover and/or gain insight into new antiviral targets. We shall evaluate for antiviral activity and cytotoxicity new series of nucleoside analogs (benzimidazoles and indoles) and related heterocyclics prepared in the laboratory of Dr. Townsend (Research Project I) and a very different series of nucleoside analogs (methylenecyclopropane analogs and related prodrugs) prepared in the laboratory of Dr. Zemlicka (Research Project 2). All compounds will be tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type I (HSV-I). The most promising compounds also will be tested against clinical isolates and HCMV strains which are resistant to ganciclovir, benzimidazole nucleosides, or methylenecyclopropane analogs. A broader evaluation against other herpesviruses will be performed in the Scientific Core laboratory. New compounds which are active and low in cytotoxicity - plus existing compounds from our laboratories that appear to act by unique mechanisms - shall be studied extensively to determine their mode of action and to determine if they affect a new antiviral target. Compounds with the best overall profiles will be sent to our Scientific Core for in vivo studies. The modes of antiviral action of compounds discovered as described above, and the modes of action of existing antiviral compounds which we have discovered, will be investigated using selected biochemical characterization, Isolation of drug-resistant mutant virus, phenotypic and genotypic characterization of mutant virus, drug resistance mapping, site- directed mutagenesis, and in vitro drug metabolism with wild-type and resistant viruses. We already have found that the different series of compounds described herein act by different mechanisms. They can be categorized by the time in the viral replication cycle at which they act. For example, compounds have been found which (i) act early in the HCMV replication cycle (certain benzimidazoles), (ii) inhibit viral DNA synthesis (methylenecyclopropane analogs) and (iii) stop viral DNA processing (other benzimidazoles and indoles). We have identified the viral gene products (UL56, UL89) targeted by some of these compounds but have not yet identified those targeted by others. These studies will extend our knowledge about certain drug targets and help to identify new ones.
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