Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography.

Autor:	Borsatto A; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.; ISPSO, University of Geneva, Geneva, Switzerland., Akkad O; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.; ISPSO, University of Geneva, Geneva, Switzerland., Galdadas I; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.; ISPSO, University of Geneva, Geneva, Switzerland., Ma S; School of Pharmacy, University College London, London, United Kingdom., Damfo S; School of Pharmacy, University College London, London, United Kingdom., Haider S; School of Pharmacy, University College London, London, United Kingdom.; UCL Centre for Advanced Research Computing, University College London, London, United Kingdom., Kozielski F; School of Pharmacy, University College London, London, United Kingdom., Estarellas C; Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, and Institute of Theoretical and Computational Chemistry, University of Barcelona, Barcelona, Spain., Gervasio FL; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.; ISPSO, University of Geneva, Geneva, Switzerland.; Chemistry Department, University College London, London, United Kingdom.; Institute of Structural and Molecular Biology, University College London, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2022 Nov 22; Vol. 11. Date of Electronic Publication: 2022 Nov 22.
DOI:	10.7554/eLife.81167
Abstrakt:	Non-structural protein 1 (Nsp1) is a main pathogenicity factor of α - and β - 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 β - coronaviruses. Competing Interests: AB, OA, IG, SM, SD, FK, CE, FG No competing interests declared, SH Reviewing editor, eLife (© 2022, Borsatto et al.)
Databáze:	MEDLINE
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