Abstract
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.
Highlights
Severe acute respiratory coronavirus 2 (SARS-CoV-2) is an important human pathogen and the causative agent of coronavirus disease 2019 (COVID-19)
Previous experiments showed that enisamium (Figure 1A) can efficiently inhibit influenza virus replication in normal human bronchial epithelial (NHBE) cultures and
We previously showed that enisamium is metabolized to VR17-04, and that VR17Bond Formation can block influenza A virus RNA polymerase activity
Summary
Severe acute respiratory coronavirus 2 (SARS-CoV-2) is an important human pathogen and the causative agent of coronavirus disease 2019 (COVID-19). Vaccines are available to prevent the spread of SARS-CoV-2, and several antiviral strategies, such as treatment with remdesivir or reconvalescent plasma, have received FDA approval or emergency use approval. The development of additional strategies remains necessary, because of the continuous emergence of variants of concern (VOC) and current antiviral treatments can only be delivered intravenously. A key target for novel drug screening is the RNA polymerase of SARS-CoV-2 [1,2,3,4]. SARS-CoV-2 is a betacoronavirus and contains a positive-sense, non-segmented RNA genome of around 30 kilobases [5,6].
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