The NSP14/NSP10 RNA repair complex as a Pan-coronavirus therapeutic target

• Published in: Cell death and differentiation Vol. 29; no. 2; pp. 285 - 292
• Main Authors: Rona, Gergely, Zeke, Andras, Miwatani-Minter, Bearach, de Vries, Maren, Kaur, Ramanjit, Schinlever, Austin, Garcia, Sheena Faye, Goldberg, Hailey V., Wang, Hui, Hinds, Thomas R., Bailly, Fabrice, Zheng, Ning, Cotelle, Philippe, Desmaële, Didier, Landau, Nathaniel R., Dittmann, Meike, Pagano, Michele
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2022; Nature Publishing Group
• Subjects: 13/1; 13/106; 14; 631/326; 631/45/607/1159; 692/699/255; 82/47; 82/83; A549 Cells; Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - pharmacology; Alanine - analogs & derivatives; Alanine - pharmacology; Antiviral agents; Antiviral Agents - pharmacology; Antiviral drugs; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Chemical Sciences; Coronaviruses; Exonuclease; Exoribonucleases - metabolism; Humans; Life Sciences; Pandemics; SARS-CoV-2 - drug effects; SARS-CoV-2 - enzymology; Severe acute respiratory syndrome coronavirus 2; Stem Cells; Therapeutic applications; Therapeutic targets; Viral Nonstructural Proteins - metabolism; Viral Regulatory and Accessory Proteins - metabolism; Virus Replication - drug effects; Microbiology; Infectious diseases; DNA repair enzymes
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/s41418-021-00900-1

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.