期刊
CELL DEATH AND DIFFERENTIATION
卷 29, 期 2, 页码 285-292出版社
SPRINGERNATURE
DOI: 10.1038/s41418-021-00900-1
关键词
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资金
- National Institutes of Health (NIH) [DA046100, AI122390, AI120898]
- NIH [R01AI143639, R21AI139374, R01CA76584, R35GM136250]
- G. Harold and Leila Y. Mathers Charitable Foundation
A novel NSP14-NSP10 inhibitor, sofalcone, was found to enhance the efficacy of remdesivir and exhibit inhibitory activity against various coronaviruses in vitro. This provides proof-of-concept for the NSP14 complex as a 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 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.
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