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
em En
| MEDLINE
| ID: mdl-33655614
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antivirais
/
Inibidores de Proteases
/
Proteases 3C de Coronavírus
/
SARS-CoV-2
/
Tratamento Farmacológico da COVID-19
/
Nitrilas
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article