Hepatitis B virus (HBV) chronically infects rt250 million people worldwide and kills rt850,000 annually worldwide. Therapy primarily employs nucleos(t)ide analog drugs that target the viral DNA polymerase. Current therapy is inadequate and new therapies are urgently needed. This hit-to-lead project will generate a Lead series of small molecules of highly active inhibitors of the underexploited HBV RNaseH target. These novel compounds will be generated by expanding upon a set of newly identified ?-Hydroxytropolones (?HTs) utilizing a recently developed superior RNaseH assay.Aim 1: Modification of ?-Hydroxytropolones (?HTs) to improve efficacy and therapeutic index: A series of novel ?HTs will be synthesized and assessed for HBV replication inhibition, suppression of HBV RNaseH activity, and cytotoxicity. Compound synthesis will be iterative so that early results can inform later sets of compounds.Aim 2: ?HTs with predefined pharmacological parameters and selectivity will be identified: Preliminary in vitro pharmacology such as metabolic stability will instruct selection of the best compounds for future Lead Optimization and Drug Development. The ultimate goal is to generate new therapeutic drug candidate(s) for the treatment of HBV infections which act via a new mechanism of action versus standard nucleoside analog therapy.
