| Summary: | 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<sup>pro</sup>) was inhibited by ATV, with Morrison’s inhibitory constant (K<sub>i</sub>) 1.5-fold higher than GC376 (a positive control) dependent of the catalytic water (H<sub>2</sub>O<sub>cat</sub>) content. ATV was a competitive inhibitor, increasing the M<sup>pro</sup>’s Michaelis–Menten (K<sub>m</sub>) 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<sup>pro</sup>/ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease.
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