The NSP14/NSP10 RNA repair complex as a Pan-coronavirus therapeutic target
Gergely Róna, András Zeke, Bearach Miwatani-Minter, Maren de Vries, Ramanjit Kaur, Austin R. Schinlever, Sheena Faye Garcia, Hailey V. Goldberg, Hui Wang, Thomas R. Hinds, Fabrice Bailly, Ning Zheng, Philippe Cotelle, Didier Desmaële, Nathaniel R. Landau, Meike Dittmann, Michele Pagano
Abstract
The risk of zoonotic coronavirus spillover into the human population, as highlighted by the SARS-CoV-2 pandemic, demands the development of pan-coronavirus antivirals. The efficacy of existing antiviral ribonucleoside/ribonucleotide analogs, such as remdesivir, is decreased by the viral proofreading exonuclease NSP14-NSP10 complex. Here, using a novel assay and in silico modeling and screening, we identified NSP14-NSP10 inhibitors that increase remdesivir's potency. A model compound, sofalcone, both inhibits the exonuclease activity of SARS-CoV-2, SARS-CoV, and MERS-CoV in vitro, and synergistically enhances the antiviral effect of remdesivir, suppressing the replication of SARS-CoV-2 and the related human coronavirus OC43. The validation of top hits from our primary screenings using cellular systems provides proof-of-concept for the NSP14 complex as a therapeutic target.