TY - JOUR T1 - Atazanavir is a competitive inhibitor of SARS-CoV-2 M<sup>pro</sup>, impairing variants replication <em>in vitro</em> and <em>in vivo</em> JF - bioRxiv DO - 10.1101/2021.11.24.469775 SP - 2021.11.24.469775 AU - Otávio Augusto Chaves AU - Carolina Q. Sacramento AU - André C. Ferreira AU - Mayara Mattos AU - Natalia Fintelman-Rodrigues AU - Jairo R. Temerozo AU - Douglas Pereira Pinto AU - Gabriel P. E. da Silveira AU - Laís Bastos da Fonseca AU - Heliana Martins Pereira AU - Aluana Santana Carlos AU - Joana da Costa Pinto d’Ávila AU - João P.B. Viola AU - Robson Q. Monteiro AU - Leonardo Vazquez AU - Patrícia T. Bozza AU - Hugo Caire Castro-Faria-Neto AU - Thiago Moreno L. Souza Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/11/24/2021.11.24.469775.abstract N2 - Atazanavir (ATV) has already been considered as a potential repurposing drug to 2019 coronavirus disease (COVID-19), however, there are controversial reports on its mechanism of action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the pre-clinical chain of experiments: enzymatic, molecular docking, cell-based, and in vivo assays, it is demonstrated here that both SARS-CoV-2 B.1 lineage and variant of concern gamma are susceptible to this antiretroviral. Enzymatic assays and molecular docking calculations showed that SARS-CoV-2 main protease (Mpro) was inhibited by ATV, with Morrison’s inhibitory constant (Ki) 1.5-fold higher than boceprevir (GC376, a positive control). ATV was a competitive inhibition, increasing the Mpro’s Michaelis-Menten (Km) more than 6-fold. Cell-based assays indicated that SARS-CoV-2 gamma is more susceptible to ATV than its predecessor strain B.1. Using oral administration of ATV in mice to reach plasmatic exposure similar to humans, transgenic mice expression in human angiotensin converting enzyme 2 (K18-hACE2) were partially protected against lethal challenge with SARS-CoV-2 gamma. Moreover, less cell death and inflammation were observed in the lung from infected and treated mice. Our studies may contribute to a better comprehension of the Mpro/ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease.Competing Interest StatementThe authors have declared no competing interest. ER -