Identification of Vitamin K3 and its analogues as covalent inhibitors of SARS-CoV-2 3CLpro.
Int J Biol Macromol
; 183: 182-192, 2021 Jul 31.
Article
in English
| MEDLINE | ID: covidwho-1305238
ABSTRACT
After the emergence of the pandemic, repurposed drugs have been considered as a quicker way of finding potential antiviral agents. SARS-CoV-2 3CLpro is essential for processing the viral polyproteins into mature non-structural proteins, making it an attractive target for developing antiviral agents. Here we show that Vitamin K3 screened from the FDA-Approved Drug Library containing an array of 1,018 compounds has potent inhibitory activity against SARS-CoV-2 3CLpro with the IC50 value of 4.78 ± 1.03 µM, rather than Vitamin K1, K2 and K4. Next, the time-dependent inhibitory experiment was carried out to confirm that Vitamin K3 could form the covalent bond with SARS-CoV-2 3CLpro. Then we analyzed the structure-activity relationship of Vitamin K3 analogues and identified 5,8-dihydroxy-1,4-naphthoquinone with 9.8 times higher inhibitory activity than Vitamin K3. Further mass spectrometric analysis and molecular docking study verified the covalent binding between Vitamin K3 or 5,8-dihydroxy-1,4-naphthoquinone and SARS-CoV-2 3CLpro. Thus, our findings provide valuable information for further optimization and design of novel inhibitors based on Vitamin K3 and its analogues, which may have the potential to fight against SARS-CoV-2.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Cysteine Proteinase Inhibitors
/
Vitamin K 3
/
Coronavirus 3C Proteases
/
SARS-CoV-2
Limits:
Humans
Language:
English
Journal:
Int J Biol Macromol
Year:
2021
Document Type:
Article
Affiliation country:
J.ijbiomac.2021.04.129
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