NMR Spectroscopy of the Main Protease of SARS-CoV-2 and Fragment-Based Screening Identify Three Protein Hotspots and an Antiviral Fragment.
Angew Chem Int Ed Engl
; 60(48): 25428-25435, 2021 11 22.
Article
in English
| MEDLINE | ID: covidwho-1490696
ABSTRACT
The main protease (3CLp) of the SARS-CoV-2, the causative agent for the COVID-19 pandemic, is one of the main targets for drug development. To be active, 3CLp relies on a complex interplay between dimerization, active site flexibility, and allosteric regulation. The deciphering of these mechanisms is a crucial step to enable the search for inhibitors. In this context, using NMR spectroscopy, we studied the conformation of dimeric 3CLp from the SARS-CoV-2 and monitored ligand binding, based on NMR signal assignments. We performed a fragment-based screening that led to the identification of 38 fragment hits. Their binding sites showed three hotspots on 3CLp, two in the substrate binding pocket and one at the dimer interface. F01 is a non-covalent inhibitor of the 3CLp and has antiviral activity in SARS-CoV-2 infected cells. This study sheds light on the complex structure-function relationships of 3CLp and constitutes a strong basis to assist in developing potent 3CLp inhibitors.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Cysteine Proteinase Inhibitors
/
Small Molecule Libraries
/
Coronavirus 3C Proteases
/
SARS-CoV-2
Type of study:
Prognostic study
Topics:
Traditional medicine
Limits:
Animals
Language:
English
Journal:
Angew Chem Int Ed Engl
Year:
2021
Document Type:
Article
Affiliation country:
Anie.202109965
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