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 (M pro ) was inhibited by ATV, with Morrison’s inhibitory constant (K i ) 1.5-fold higher than GC376 (a positive control) dependent of the catalytic water (H 2 O cat ) content. ATV was a competitive inhibitor, increasing the M pro ’s Michaelis–Menten (K m ) 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 M pro /ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease.
【저자키워드】 COVID-19, SARS-CoV-2, molecular docking, pharmacokinetics, repurposing drugs, Protease inhibitor, Atazanavir, 【초록키워드】 Inflammation, coronavirus, variant, lung, protease, SARS-CoV-2 main protease, mice, humans, Lineage, Effectiveness, 2019 coronavirus disease, in vivo, cell death, inhibitor, mechanism of action, expression, K18-hACE2, Interaction, administration, specific inhibitor, acute respiratory syndrome, enzyme, M pro, transgenic mice, positive control, B.1 lineage, inhibitory, antiretroviral, susceptible, indicated, assays, inhibited, treated, less, contribute, demonstrated, catalytic, 【제목키워드】 M pro,