New paper on the revealing of new druggable cryptic pockets in the Nsp-1 of SARS-CoV-2 and other β-coronaviruses.

To uncover this cryptic and partially hidden pocket, we carried out simulations using algorithms that we developed. These results pave the way for the development of new treatments targeting the Nsp1 protein, not only against SARS-CoV-2 and its variants but also against other coronaviruses in which Nsp1 is present.

A. Borsatto, O. Akkad, I. Galdadas, S. Ma, S. Damfo, S. Haider, F. Kozielski, C. Estarellas, F. L. Gervasio. Revealing druggable cryptic pockets in the Nsp-1 of SARS-CoV-2 and other 2 β-coronaviruses by simulations and crystallography. eLife 2022;11:e81167. 10.7554/eLife.81167.


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.

Press Release:

· (fr): Découverte d’une nouvelle cible pour attaquer le coronavirus

· (en): Covid: Spike protein is no longer only target

· (es): COVID-19: encuentran una alternativa a Spike como diana farmacológica