SARS-CoV-2 Mpro inhibitors and activity-based probes for patient-sample imaging.
Nat Chem Biol
; 17(2): 222-228, 2021 02.
Article
in English
| MEDLINE | ID: covidwho-899948
ABSTRACT
In December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed. Currently, there is no effective antiviral treatment for COVID-19. To address this emerging problem, we focused on the SARS-CoV-2 main protease that constitutes one of the most attractive antiviral drug targets. We have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 main proteases. On the basis of these findings, we designed and synthesized a potent SARS-CoV-2 inhibitor (Ac-Abu-DTyr-Leu-Gln-VS, half-maximal effective concentration of 3.7 µM) and two activity-based probes, for one of which we determined the crystal structure of its complex with the SARS-CoV-2 Mpro. We visualized active SARS-CoV-2 Mpro in nasopharyngeal epithelial cells of patients suffering from COVID-19 infection. The results of our work provide a structural framework for the design of inhibitors as antiviral agents and/or diagnostic tests.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Protease Inhibitors
/
Epithelial Cells
/
Coronavirus 3C Proteases
/
SARS-CoV-2
/
COVID-19
Type of study:
Diagnostic study
Limits:
Humans
Language:
English
Journal:
Nat Chem Biol
Journal subject:
Biology
/
Chemistry
Year:
2021
Document Type:
Article
Affiliation country:
S41589-020-00689-z
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