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

Authors :
Otávio Augusto Chaves
Carolina Q. Sacramento
André C. Ferreira
Mayara Mattos
Natalia Fintelman-Rodrigues
Jairo R. Temerozo
Leonardo Vazquez
Douglas Pereira Pinto
Gabriel P. E. da Silveira
Laís Bastos da Fonseca
Heliana Martins Pereira
Aluana Santana Carlos
Joana C. d’Avila
João P. B. Viola
Robson Q. Monteiro
Patrícia T. Bozza
Hugo Caire Castro-Faria-Neto
Thiago Moreno L. Souza
Source :
Pharmaceuticals, Vol 15, Iss 1, p 21 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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.

Details

Language :
English
ISSN :
14248247
Volume :
15
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Pharmaceuticals
Publication Type :
Academic Journal
Accession number :
edsdoj.fecc3e0ccd4849ebbf28cd15d63ee8a1
Document Type :
article
Full Text :
https://doi.org/10.3390/ph15010021