The NSP14/NSP10 RNA repair complex as a Pan-coronavirus therapeutic target.
Cell Death Differ
; 29(2): 285-292, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-34862481
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Monofosfato de Adenosina
/
Proteínas não Estruturais Virais
/
Alanina
/
Exorribonucleases
/
Proteínas Virais Reguladoras e Acessórias
/
SARS-CoV-2
Limite:
Humans
Idioma:
En
Revista:
Cell Death Differ
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos