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Atazanavir Is a Competitive Inhibitor of SARS-CoV-2 Mpro, Impairing Variants Replication In Vitro and In Vivo

2021; Multidisciplinary Digital Publishing Institute; Volume: 15; Issue: 1 Linguagem: Inglês

10.3390/ph15010021

1424-8247

Otávio Augusto Chaves, Carolina Q. Sacramento, André C. Ferreira, Mayara Mattos, Natália Fintelman-Rodrigues, Jairo R. Temerozo, Leonardo Vázquez, Douglas Pereira Pinto, Gabriel Parreiras Estolano da Silveira, Laís Bastos da Fonseca, Heliana Martins Pereira, Aluana Santana Carlos, Joana C. d’Avila, João P. B. Viola, Robson Q. Monteiro, Patrı́cia T. Bozza, Hugo C. Castro‐Faria‐Neto, Thiago Moreno L. Souza,

COVID-19 Clinical Research Studies

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 GC376 (a positive control) dependent of the catalytic water (H2Ocat) content. ATV was a competitive inhibitor, increasing the Mpro's Michaelis-Menten (Km) more than sixfold. Cell-based assays indicated that different lineages of SARS-CoV-2 is susceptible to ATV. 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.