tetano
Editor, Senior Moderator
Pharmaceuticals (Basel)
. 2021 Dec 24;15(1):21.
doi: 10.3390/ph15010021.
Atazanavir Is a Competitive Inhibitor of SARS-CoV-2 M [SUP]pro[/SUP], Impairing Variants Replication In Vitro and In Vivo
Otávio Augusto Chaves[SUP] 1 2 [/SUP], Carolina Q Sacramento[SUP] 1 2 [/SUP], André C Ferreira[SUP] 1 2 3 [/SUP], Mayara Mattos[SUP] 1 2 [/SUP], Natalia Fintelman-Rodrigues[SUP] 1 2 [/SUP], Jairo R Temerozo[SUP] 4 5 [/SUP], Leonardo Vazquez[SUP] 1 [/SUP], Douglas Pereira Pinto[SUP] 6 [/SUP], Gabriel P E da Silveira[SUP] 6 [/SUP], Laís Bastos da Fonseca[SUP] 6 [/SUP], Heliana Martins Pereira[SUP] 6 [/SUP], Aluana Santana Carlos[SUP] 3 [/SUP], Joana C d'Avila[SUP] 1 3 [/SUP], João P B Viola[SUP] 7 [/SUP], Robson Q Monteiro[SUP] 8 [/SUP], Patrícia T Bozza[SUP] 1 [/SUP], Hugo Caire Castro-Faria-Neto[SUP] 1 [/SUP], Thiago Moreno L Souza[SUP] 1 2 [/SUP]
Affiliations
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 (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.
Keywords: COVID-19; SARS-CoV-2; atazanavir; molecular docking; pharmacokinetics; protease inhibitor; repurposing drugs.
. 2021 Dec 24;15(1):21.
doi: 10.3390/ph15010021.
Atazanavir Is a Competitive Inhibitor of SARS-CoV-2 M [SUP]pro[/SUP], Impairing Variants Replication In Vitro and In Vivo
Otávio Augusto Chaves[SUP] 1 2 [/SUP], Carolina Q Sacramento[SUP] 1 2 [/SUP], André C Ferreira[SUP] 1 2 3 [/SUP], Mayara Mattos[SUP] 1 2 [/SUP], Natalia Fintelman-Rodrigues[SUP] 1 2 [/SUP], Jairo R Temerozo[SUP] 4 5 [/SUP], Leonardo Vazquez[SUP] 1 [/SUP], Douglas Pereira Pinto[SUP] 6 [/SUP], Gabriel P E da Silveira[SUP] 6 [/SUP], Laís Bastos da Fonseca[SUP] 6 [/SUP], Heliana Martins Pereira[SUP] 6 [/SUP], Aluana Santana Carlos[SUP] 3 [/SUP], Joana C d'Avila[SUP] 1 3 [/SUP], João P B Viola[SUP] 7 [/SUP], Robson Q Monteiro[SUP] 8 [/SUP], Patrícia T Bozza[SUP] 1 [/SUP], Hugo Caire Castro-Faria-Neto[SUP] 1 [/SUP], Thiago Moreno L Souza[SUP] 1 2 [/SUP]
Affiliations
- PMID: 35056078
- DOI: 10.3390/ph15010021
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 (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.
Keywords: COVID-19; SARS-CoV-2; atazanavir; molecular docking; pharmacokinetics; protease inhibitor; repurposing drugs.