Challenges of short substrate analogues as SARS-CoV-2 main protease inhibitors.
Bioorg Med Chem Lett
; 50: 128333, 2021 10 15.
Article
in English
| MEDLINE | ID: covidwho-1363893
ABSTRACT
Specific anti-coronaviral drugs complementing available vaccines are urgently needed to fight the COVID-19 pandemic. Given its high conservation across the betacoronavirus genus and dissimilarity to human proteases, the SARS-CoV-2 main protease (Mpro) is an attractive drug target. SARS-CoV-2 Mpro inhibitors have been developed at unprecedented speed, most of them being substrate-derived peptidomimetics with cysteine-modifying warheads. In this study, Mpro has proven resistant towards the identification of high-affinity short substrate-derived peptides and peptidomimetics without warheads. 20 cyclic and linear substrate analogues bearing natural and unnatural residues, which were predicted by computational modelling to bind with high affinity and designed to establish structure-activity relationships, displayed no inhibitory activity at concentrations as high as 100 µM. Only a long linear peptide covering residues P6 to P5' displayed moderate inhibition (Ki = 57 µM). Our detailed findings will inform current and future drug discovery campaigns targeting Mpro.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Protease Inhibitors
/
Coronavirus 3C Proteases
/
SARS-CoV-2
/
COVID-19
Type of study:
Prognostic study
Topics:
Vaccines
Limits:
Humans
Language:
English
Journal:
Bioorg Med Chem Lett
Journal subject:
Biochemistry
/
Chemistry
Year:
2021
Document Type:
Article
Affiliation country:
J.bmcl.2021.128333
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