Targeting the Main Protease of SARS-CoV-2: From the Establishment of High Throughput Screening to the Design of Tailored Inhibitors.
Angew Chem Int Ed Engl
; 60(18): 10423-10429, 2021 04 26.
Article
in English
| MEDLINE | ID: covidwho-1114156
ABSTRACT
The main protease of SARS-CoV-2 (Mpro ), the causative agent of COVID-19, constitutes a significant drug target. A new fluorogenic substrate was kinetically compared to an internally quenched fluorescent peptide and shown to be ideally suitable for high throughput screening with recombinantly expressed Mpro . Two classes of protease inhibitors, azanitriles and pyridyl esters, were identified, optimized and subjected to in-depth biochemical characterization. Tailored peptides equipped with the unique azanitrile warhead exhibited concomitant inhibition of Mpro and cathepsinâ
L, a protease relevant for viral cell entry. Pyridyl indole esters were analyzed by a positional scanning. Our focused approach towards Mpro inhibitors proved to be superior to virtual screening. With two irreversible inhibitors, azanitrile 8 (kinac /Ki =37 500â
m-1 s-1 , Ki =24.0â
nm) and pyridyl ester 17 (kinac /Ki =29 100â
m-1 s-1 , Ki =10.0â
nm), promising drug candidates for further development have been discovered.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Protease Inhibitors
/
Coronavirus 3C Proteases
/
SARS-CoV-2
/
COVID-19 Drug Treatment
/
Nitriles
Limits:
Humans
Language:
English
Journal:
Angew Chem Int Ed Engl
Year:
2021
Document Type:
Article
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