Lifecycle modelling systems support inosine monophosphate dehydrogenase (IMPDH) as a pro-viral factor and antiviral target for New World arenaviruses

Antiviral Research
Eric C DunhamAllison Groseth

Abstract

Infection with Junín virus (JUNV) is currently being effectively managed in the endemic region using a combination of targeted vaccination and plasma therapy. However, the long-term sustainability of plasma therapy is unclear and similar resources are not available for other New World arenaviruses. As a result, there has been renewed interest regarding the potential of drug-based therapies. To facilitate work on this issue, we present the establishment and subsequent optimization of a JUNV minigenome system to a degree suitable for high-throughput miniaturization, thereby providing a screening platform focused solely on factors affecting RNA synthesis. Using this tool, we conducted a limited drug library screen and identified AVN-944, a non-competitive inosine monophosphate dehydrogenase (IMPDH) inhibitor, as an inhibitor of arenavirus RNA synthesis. We further developed a transcription and replication competent virus-like particle (trVLP) system based on these minigenomes and used it to screen siRNAs against IMPDH, verifying its role in supporting arenavirus RNA synthesis. The antiviral effect of AVN-944, as well as siRNA inhibition, on JUNV RNA synthesis supports that, despite playing only a minor role in the activity of riba...Continue Reading

Citations

Mar 29, 2019·Frontiers in Immunology·Morgan E Brisse, Hinh Ly
Sep 24, 2020·Viruses·Desarey Morales VasquezLuis Martinez-Sobrido
Jan 21, 2021·Antimicrobial Agents and Chemotherapy·Shawn HerringStephen J Polyak
Jul 30, 2019·Current Opinion in Virology·Brett BeitzelGustavo Palacios
Jan 23, 2019·Antiviral Research·Anne LeskeAllison Groseth

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