tetano
Editor, Senior Moderator
Cell Death Differ
. 2021 Dec 3.
doi: 10.1038/s41418-021-00900-1. Online ahead of print.
The NSP14/NSP10 RNA repair complex as a Pan-coronavirus therapeutic target
Gergely Rona[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Andras Zeke[SUP] #[/SUP][SUP] 1 2 4 [/SUP], Bearach Miwatani-Minter[SUP] 1 2 [/SUP], Maren de Vries[SUP] 5 [/SUP], Ramanjit Kaur[SUP] 5 [/SUP], Austin Schinlever[SUP] 5 [/SUP], Sheena Faye Garcia[SUP] 1 2 [/SUP], Hailey V Goldberg[SUP] 1 2 [/SUP], Hui Wang[SUP] 6 7 [/SUP], Thomas R Hinds[SUP] 6 7 [/SUP], Fabrice Bailly[SUP] 8 [/SUP], Ning Zheng[SUP] 6 7 [/SUP], Philippe Cotelle[SUP] 8 9 [/SUP], Didier Desmaële[SUP] 10 [/SUP], Nathaniel R Landau[SUP] 5 [/SUP], Meike Dittmann[SUP] 11 [/SUP], Michele Pagano[SUP] 12 13 14 [/SUP]
Affiliations
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.
. 2021 Dec 3.
doi: 10.1038/s41418-021-00900-1. Online ahead of print.
The NSP14/NSP10 RNA repair complex as a Pan-coronavirus therapeutic target
Gergely Rona[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Andras Zeke[SUP] #[/SUP][SUP] 1 2 4 [/SUP], Bearach Miwatani-Minter[SUP] 1 2 [/SUP], Maren de Vries[SUP] 5 [/SUP], Ramanjit Kaur[SUP] 5 [/SUP], Austin Schinlever[SUP] 5 [/SUP], Sheena Faye Garcia[SUP] 1 2 [/SUP], Hailey V Goldberg[SUP] 1 2 [/SUP], Hui Wang[SUP] 6 7 [/SUP], Thomas R Hinds[SUP] 6 7 [/SUP], Fabrice Bailly[SUP] 8 [/SUP], Ning Zheng[SUP] 6 7 [/SUP], Philippe Cotelle[SUP] 8 9 [/SUP], Didier Desmaële[SUP] 10 [/SUP], Nathaniel R Landau[SUP] 5 [/SUP], Meike Dittmann[SUP] 11 [/SUP], Michele Pagano[SUP] 12 13 14 [/SUP]
Affiliations
- PMID: 34862481
- DOI: 10.1038/s41418-021-00900-1
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.