tetano
Editor, Senior Moderator
Nat Commun
. 2022 Jun 21;13(1):3556.
doi: 10.1038/s41467-022-31210-w.
Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance
Ala M Shaqra[SUP] #[/SUP][SUP] 1 [/SUP], Sarah N Zvornicanin[SUP] #[/SUP][SUP] 1 [/SUP], Qiu Yu J Huang[SUP] #[/SUP][SUP] 1 [/SUP], Gordon J Lockbaum[SUP] 1 [/SUP], Mark Knapp[SUP] 2 [/SUP], Laura Tandeske[SUP] 2 [/SUP], David T Bakan[SUP] 2 [/SUP], Julia Flynn[SUP] 1 [/SUP], Daniel N A Bolon[SUP] 1 [/SUP], Stephanie Moquin[SUP] 2 [/SUP], Dustin Dovala[SUP] 2 [/SUP], Nese Kurt Yilmaz[SUP] 3 [/SUP], Celia A Schiffer[SUP] 4 [/SUP]
Affiliations
Abstract
Coronaviruses can evolve and spread rapidly to cause severe disease morbidity and mortality, as exemplified by SARS-CoV-2 variants of the COVID-19 pandemic. Although currently available vaccines remain mostly effective against SARS-CoV-2 variants, additional treatment strategies are needed. Inhibitors that target essential viral enzymes, such as proteases and polymerases, represent key classes of antivirals. However, clinical use of antiviral therapies inevitably leads to emergence of drug resistance. In this study we implemented a strategy to pre-emptively address drug resistance to protease inhibitors targeting the main protease (M[SUP]pro[/SUP]) of SARS-CoV-2, an essential enzyme that promotes viral maturation. We solved nine high-resolution cocrystal structures of SARS-CoV-2 M[SUP]pro[/SUP] bound to substrate peptides and six structures with cleavage products. These structures enabled us to define the substrate envelope of M[SUP]pro[/SUP], map the critical recognition elements, and identify evolutionarily vulnerable sites that may be susceptible to resistance mutations that would compromise binding of the newly developed M[SUP]pro[/SUP] inhibitors. Our results suggest strategies for developing robust inhibitors against SARS-CoV-2 that will retain longer-lasting efficacy against this evolving viral pathogen.
. 2022 Jun 21;13(1):3556.
doi: 10.1038/s41467-022-31210-w.
Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance
Ala M Shaqra[SUP] #[/SUP][SUP] 1 [/SUP], Sarah N Zvornicanin[SUP] #[/SUP][SUP] 1 [/SUP], Qiu Yu J Huang[SUP] #[/SUP][SUP] 1 [/SUP], Gordon J Lockbaum[SUP] 1 [/SUP], Mark Knapp[SUP] 2 [/SUP], Laura Tandeske[SUP] 2 [/SUP], David T Bakan[SUP] 2 [/SUP], Julia Flynn[SUP] 1 [/SUP], Daniel N A Bolon[SUP] 1 [/SUP], Stephanie Moquin[SUP] 2 [/SUP], Dustin Dovala[SUP] 2 [/SUP], Nese Kurt Yilmaz[SUP] 3 [/SUP], Celia A Schiffer[SUP] 4 [/SUP]
Affiliations
- PMID: 35729165
- DOI: 10.1038/s41467-022-31210-w
Abstract
Coronaviruses can evolve and spread rapidly to cause severe disease morbidity and mortality, as exemplified by SARS-CoV-2 variants of the COVID-19 pandemic. Although currently available vaccines remain mostly effective against SARS-CoV-2 variants, additional treatment strategies are needed. Inhibitors that target essential viral enzymes, such as proteases and polymerases, represent key classes of antivirals. However, clinical use of antiviral therapies inevitably leads to emergence of drug resistance. In this study we implemented a strategy to pre-emptively address drug resistance to protease inhibitors targeting the main protease (M[SUP]pro[/SUP]) of SARS-CoV-2, an essential enzyme that promotes viral maturation. We solved nine high-resolution cocrystal structures of SARS-CoV-2 M[SUP]pro[/SUP] bound to substrate peptides and six structures with cleavage products. These structures enabled us to define the substrate envelope of M[SUP]pro[/SUP], map the critical recognition elements, and identify evolutionarily vulnerable sites that may be susceptible to resistance mutations that would compromise binding of the newly developed M[SUP]pro[/SUP] inhibitors. Our results suggest strategies for developing robust inhibitors against SARS-CoV-2 that will retain longer-lasting efficacy against this evolving viral pathogen.