Enisamium is a small molecule inhibitor of the influenza A virus and SARS-CoV-2 RNA polymerases

• Published in: bioRxiv 2020-01
• Main Authors: Walker, Alexander, Fan, Haitian, Keown, Jeremy R, Margitich, Victor, Grimes, Jonathan M, Fodor, Ervin, Aartjan Jw Te Velthuis
• Format: Article
• Language: English
• Subjects: Cell culture; Coronaviruses; COVID-19; DNA-directed RNA polymerase; Influenza; Influenza A; Influenza B; Metabolites; Microbiology; Pandemics; Respiratory diseases; RNA polymerase; RNA viruses; Severe acute respiratory syndrome coronavirus 2; Strains (organisms); Therapeutic targets; Transcription; Vaccines; Viruses
• ISSN: 2692-8205
• DOI: 10.1101/2020.04.21.053017

Influenza A virus and coronavirus strains cause a mild to severe respiratory disease that can result in death. Although vaccines exist against circulating influenza A viruses, such vaccines are ineffective against emerging pandemic influenza A viruses. Currently, no vaccine exists against coronavirus infections, including pandemic SARS-CoV-2, the causative agent of the Coronavirus Disease 2019 (COVID-19). To combat these RNA virus infections, alternative antiviral strategies are needed. A key drug target is the viral RNA polymerase, which is responsible for viral RNA synthesis. In January 2020, the World Health Organisation identified enisamium as a candidate therapeutic against SARS-CoV-2. Enisamium is an isonicotinic acid derivative that is an inhibitor of multiple influenza B and A virus strains in cell culture and clinically approved in 11 countries. Here we show using in vitro assays that enisamium and its putative metabolite, VR17-04, inhibit the activity of the influenza virus and the SARS-CoV-2 RNA polymerase. VR17-04 displays similar efficacy against the SARS-CoV-2 RNA polymerase as the nucleotide analogue remdesivir triphosphate. These results suggest that enisamium is a broad-spectrum small molecule inhibitor of RNA virus RNA synthesis, and implicate it as a possible therapeutic option for treating SARS-CoV-2 infection. Unlike remdesivir, enisamium does not require intravenous administration which may be advantageous for the development of COVID-19 treatments outside a hospital setting. Competing Interest Statement V.M. is an employee of Farmak Public Joint Stock Company, Kiev, Ukraine. Part of this research was funded by Farmak Public Joint Stock Company, Kiev, Ukraine. Footnotes * Additional data added: influenza virus infection in A549 cells; comparisons with favipiravir and remdesivir in vitro; effect vr17-04 on influenza virus transcription in vitro. These data appear in Fig. 2, 3 and 5.