Antivirals for Rare, Emerging and Endemic Viruses of the Class Bunyaviricetes

National Center For Advancing Translational Sciences

Investigators

Abstract

High-throughput Förster resonance energy transfer (FRET)-based biochemical assays for RVFV, LACV, HANV, and PTV endonucleases have been developed and screened against small molecule libraries. Cell-based Split-luciferase cellular thermal shift assays (CETSA) have been developed to further characterize inhibitor-endonuclease engagement. Two Lassa virus (LASV) minigenome systems utilizing a reporter with L-protein dependent expression have been adopted and have validated active chemotypes from the medicinal chemistry efforts. Live virus 1536well or 384well HTS assays have been developed across viruses belonging to the families Phenuiviridae, Peribunyaviridae, and Arenaviridae. In addition, collaborations with CDC have expanded to include testing of identified compounds in fully infectious LASV reporter virus and wild type isolates. Finally, the team has been continuing to work on predictive complex in vitro neural and liver spheroid infection models. The team is optimizing leads against members of the Peribunyaviridae and Arenaviridae families with evaluation of drug metabolism and pharmacokinetic (DMPK) properties, molecular modeling and informatics, and x-ray crystallographic structure-based drug design. The team has identified highly potent inhibitors against members of both families and efficacy studies in vivo are underway or planned.