Allosteric Inhibition of the SARS-CoV-2 Main Protease: Insights from Mass Spectrometry Based Assays*.
Angew Chem Int Ed Engl
; 59(52): 23544-23548, 2020 12 21.
Article
in English
| MEDLINE | ID: covidwho-728060
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
The SARS-CoV-2 main protease (Mpro ) cleaves along the two viral polypeptides to release non-structural proteins required for viral replication. MPro is an attractive target for antiviral therapies to combat the coronavirus-2019 disease. Here, we used native mass spectrometry to characterize the functional unit of Mpro . Analysis of the monomer/dimer equilibria reveals a dissociation constant of Kd =0.14±0.03â
µM, indicating MPro has a strong preference to dimerize in solution. We characterized substrate turnover rates by following temporal changes in the enzyme-substrate complexes, and screened small molecules, that bind distant from the active site, for their ability to modulate activity. These compounds, including one proposed to disrupt the dimer, slow the rate of substrate processing by ≈35 %. This information, together with analysis of the x-ray crystal structures, provides a starting point for the development of more potent molecules that allosterically regulate MPro activity.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Models, Molecular
/
Small Molecule Libraries
/
Coronavirus Protease Inhibitors
/
Coronavirus 3C Proteases
/
SARS-CoV-2
Language:
English
Journal:
Angew Chem Int Ed Engl
Year:
2020
Document Type:
Article
Affiliation country:
Anie.202010316
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