Atorvastatin effectively inhibits late replicative cycle steps of SARS-CoV-2 in vitro

Zapata-Cardona, M. I.; Florez-Alvarez, L.; Zapata-Builes, W.; Guerra-Sandoval, A.; Guerra-Almonacid, C.; Hincapie-Garcia, J.; Rugeles, M. T.; Hernandez, J. C.

doi:10.1101/2021.03.01.433498

bioRxiv · 10.1101/2021.03.01.433498

Atorvastatin effectively inhibits late replicative cycle steps of SARS-CoV-2 in vitro

Zapata-Cardona, M. I.·Florez-Alvarez, L.·Zapata-Builes, W.·Guerra-Sandoval, A.·Guerra-Almonacid, C.·Hincapie-Garcia, J.·Rugeles, M. T.·Hernandez, J. C.

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Abstract

IntroductionSARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has caused a pandemic of historic proportions and continues to spread worldwide. Currently, there is no effective therapy against this virus. This article evaluated the in vitro antiviral effect of Atorvastatin against SARS-CoV-2 and also identified the interaction affinity between Atorvastatin and three SARS-CoV-2 proteins, using in silico structure-based molecular docking approach. Materials and methodsThe antiviral activity of Atorvastatin against SARS-CoV-2 was evaluated by three different treatment strategies using a clinical isolate of SARS-CoV-2. The interaction of Atorvastatin with Spike, RNA-dependent RNA polymerase (RdRp) and 3C-like protease (3CLpro) was evaluated by molecular docking. ResultsAtorvastatin showed anti-SARS-CoV-2 activity of 79%, 54.8%, 22.6% and 25% at 31.2, 15.6, 7.9, and 3.9 {micro}M, respectively, by pre-post-treatment strategy. In addition, atorvastatin demonstrated an antiviral effect of 26.9% at 31.2 {micro}M by pre-infection treatment. This compound also inhibited SARS-CoV-2 in 66.9%, 75%, 27.9% and 29.2% at concentrations of 31.2, 15.6, 7.9, and 3.9 {micro}M, respectively, by post-infection treatment. The interaction of atorvastatin with SARS-CoV-2 Spike, RdRp and 3CL protease yielded a binding affinity of -8.5 Kcal/mol, -6.2 Kcal/mol, and -7.5 Kcal/mol, respectively. ConclusionOur study demonstrated the in vitro anti-SARS-CoV-2 activity of Atorvastatin, mainly against the late steps of the viral replicative cycle. A favorable binding affinity with viral proteins by bioinformatics methods was also shown. Due to its low cost, availability, well-established safety and tolerability, and the extensive clinical experience of atorvastatin, it could prove valuable in reducing morbidity and mortality from COVID-19. ImportanceThe COVID-19 pandemic constitutes the largest global public health crisis in a century, with enormous health and socioeconomic challenges. Therefore, it is necessary to search for specific antivirals against its causative agent (SARS-CoV-2). In this sense, the use of existing drugs may represent a useful treatment option in terms of safety, cost-effectiveness, and timeliness. Atorvastatin is widely used to prevent cardiovascular events. This compound modulates the synthesis of cholesterol, a molecule necessary in different stages of the viral replicative cycle. Our study demonstrated the antiviral potential of atorvastatin against SARS-CoV-2, using an in vitro model. Furthermore, the ability of Atorvastatin to directly interfere with three viral targets (Spike, RdRp and 3CL protease) was demonstrated by bioinformatic methods. This compound is a well-studied, low-cost, and generally well-tolerated drug, so it could be a promising antiviral for the treatment of COVID-19.

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Zapata-Cardona, M. I., Florez-Alvarez, L., Zapata-Builes, W., Guerra-Sandoval, A., Guerra-Almonacid, C., Hincapie-Garcia, J., Rugeles, M. T., Hernandez, J. C.. 2021-03-03. Atorvastatin effectively inhibits late replicative cycle steps of SARS-CoV-2 in vitro. https://doi.org/10.1101/2021.03.01.433498

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