Antivirals for Rare, Emerging and Endemic RNA Viruses

National Center For Advancing Translational Sciences

Investigators

Abstract

Inhibitors of nsP14 ExoN and MTase: Inhibition of the activities of these enzymes is predicted to effectively interfere with virus replication, and there are no reported investigational drugs with these mechanisms. The team developed a high-throughput screening assay integrating both nsP14 MTase and ExoN activities in a 1536-well format, and identified compounds with inhibitory activity toward ExoN, MTase, and both functions. A manuscript was published describing this work. Subsequent studies are examining synergistic activity between the ExoN/MTase inhibitors and a known nucleoside RdRp inhibitor. Inhibitors of RNA virus papain-like protease (PLpro): A lead optimization program coupled with mechanistic studies was undertaken to understand the data and limitations seen with the leading, previously described inhibitors of PLpro. The team is examining the effects of cell-line sensitive viral entry inhibitory effects and their impact on antiviral assays. NNIs of RdRp: RdRp is a well validated target for inhibition by nucleoside analogs, although their discovery and development are complicated by the need for anabolism of the nucleosides by the host, and competitive binding with natural nucleosides. NNIs do not have these limitations and non-nucleoside DNA polymerase inhibitors have been developed and approved for treating DNA virus infection. However, there are no approved RdRp NNIs. The team developed an HTS biochemical assay to identify NNIs and conducted both high-throughput screening and virtual screening, identifying inhibitors with on-target activity.