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

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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640510/
https://www.ncbi.nlm.nih.gov/pubmed/34862481
http://dx.doi.org/10.1038/s41418-021-00900-1
Descripción
Sumario: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.