Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.
Nat Commun
; 11(1): 5047, 2020 10 07.
Article
in English
| MEDLINE | ID: covidwho-841208
Preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
See preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
See preprint
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Peptide Fragments
/
Cysteine Endopeptidases
/
Viral Nonstructural Proteins
/
Betacoronavirus
Topics:
Vaccines
Language:
English
Journal:
Nat Commun
Journal subject:
Biology
/
Science
Year:
2020
Document Type:
Article
Affiliation country:
S41467-020-18709-w
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