Enisamium Inhibits SARS-CoV-2 RNA Synthesis

Elli, Stefano; Bojkova, Denisa; Bechtel, Marco; Vial, Thomas; Boltz, David; Muzzio, Miguel; Peng, Xinjian; Sala, Federico; Cosentino, Cesare; Goy, Andrew; Guerrini, Marco; Müller, Lutz; Cinatl, Jindrich; Margitich, Victor; te Velthuis, Aartjan J. W.

Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called coronavirus disease 2019 (COVID-19). While control of the SARS-CoV-2 spread partly depends on vaccine-induced or naturally acquired protective herd immunity, antiviral strategies are still needed to manage COVID-19. Enisamium is an inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. In vitro, enisamium acts through metabolite VR17-04 and inhibits the activity of the influenza A virus RNA polymerase. Here we show that enisamium can inhibit coronavirus infections in NHBE and Caco-2 cells, and the activity of the SARS-CoV-2 RNA polymerase in vitro. Docking and molecular dynamics simulations provide insight into the mechanism of action and indicate that enisamium metabolite VR17-04 prevents GTP and UTP incorporation. Overall, these results suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis in vitro.