Your browser doesn't support javascript.
Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other ß-coronaviruses by simulations and crystallography.
Borsatto, Alberto; Akkad, Obaeda; Galdadas, Ioannis; Ma, Shumeng; Damfo, Shymaa; Haider, Shozeb; Kozielski, Frank; Estarellas, Carolina; Gervasio, Francesco Luigi.
  • Borsatto A; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
  • Akkad O; ISPSO, University of Geneva, Geneva, Switzerland.
  • Galdadas I; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
  • Ma S; ISPSO, University of Geneva, Geneva, Switzerland.
  • Damfo S; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
  • Haider S; ISPSO, University of Geneva, Geneva, Switzerland.
  • Kozielski F; School of Pharmacy, University College London, London, United Kingdom.
  • Estarellas C; School of Pharmacy, University College London, London, United Kingdom.
  • Gervasio FL; School of Pharmacy, University College London, London, United Kingdom.
Elife ; 112022 11 22.
Article in English | MEDLINE | ID: covidwho-2217490
ABSTRACT
Non-structural protein 1 (Nsp1) is a main pathogenicity factor of α- and ß-coronaviruses. Nsp1 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suppresses the host gene expression by sterically blocking 40S host ribosomal subunits and promoting host mRNA degradation. This mechanism leads to the downregulation of the translation-mediated innate immune response in host cells, ultimately mediating the observed immune evasion capabilities of SARS-CoV-2. Here, by combining extensive molecular dynamics simulations, fragment screening and crystallography, we reveal druggable pockets in Nsp1. Structural and computational solvent mapping analyses indicate the partial crypticity of these newly discovered and druggable binding sites. The results of fragment-based screening via X-ray crystallography confirm the druggability of the major pocket of Nsp1. Finally, we show how the targeting of this pocket could disrupt the Nsp1-mRNA complex and open a novel avenue to design new inhibitors for other Nsp1s present in homologous ß-coronaviruses.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: ELife.81167

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: ELife.81167