The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus.
Bioorg Chem
; 117: 105455, 2021 12.
Article
in English
| MEDLINE | ID: covidwho-1487613
ABSTRACT
The main protease (Mpro or 3CLpro) of SARS-CoV-2 virus is a cysteine enzyme critical for viral replication and transcription, thus indicating a potential target for antiviral therapy. A recent repurposing effort has identified ebselen, a multifunctional drug candidate as an inhibitor of Mpro. Our docking of ebselen to the binding pocket of Mpro crystal structure suggests a noncovalent interaction for improvement of potency, antiviral activity and selectivity. To test this hypothesis, we designed and synthesized ebselen derivatives aimed at enhancing their non-covalent bonds within Mpro. The inhibition of Mpro by ebselen derivatives (0.3 µM) was screened in both HPLC and FRET assays. Nine ebselen derivatives (EBs) exhibited stronger inhibitory effect on Mpro with IC50 of 0.07-0.38 µM. Further evaluation of three derivatives showed that EB2-7 exhibited the most potent inhibition of SARS-CoV-2 viral replication with an IC50 value of 4.08 µM in HPAepiC cells, as compared to the prototype ebselen at 24.61 µM. Mechanistically, EB2-7 functions as a noncovalent Mpro inhibitor in LC-MS/MS assay. Taken together, our identification of ebselen derivatives with improved antiviral activity may lead to developmental potential for treatment of COVID-19 and SARS-CoV-2 infection.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Organoselenium Compounds
/
Isoindoles
/
Coronavirus 3C Proteases
/
SARS-CoV-2
Type of study:
Experimental Studies
/
Prognostic study
Limits:
Humans
Language:
English
Journal:
Bioorg Chem
Year:
2021
Document Type:
Article
Affiliation country:
J.bioorg.2021.105455
Similar
MEDLINE
...
LILACS
LIS