Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.
Nat Commun
; 11(1): 5047, 2020 10 07.
Article
em En
| MEDLINE
| ID: mdl-33028810
ABSTRACT
COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
/
Cisteína Endopeptidases
/
Proteínas não Estruturais Virais
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Betacoronavirus
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2020
Tipo de documento:
Article