The NSP14/NSP10 RNA repair complex as a Pan-coronavirus therapeutic target.
Cell Death Differ
; 29(2): 285-292, 2022 02.
Article
in English
| MEDLINE | ID: covidwho-1550276
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Adenosine Monophosphate
/
Viral Nonstructural Proteins
/
Alanine
/
Exoribonucleases
/
Viral Regulatory and Accessory Proteins
/
SARS-CoV-2
Type of study:
Prognostic study
Limits:
Humans
Language:
English
Journal:
Cell Death Differ
Year:
2022
Document Type:
Article
Affiliation country:
S41418-021-00900-1
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