Identification of SARS-CoV-2 Mpro inhibitors containing P1' 4-fluorobenzothiazole moiety highly active against SARS-CoV-2.
Nat Commun
; 14(1): 1076, 2023 02 25.
Artículo
en Inglés
| MEDLINE | ID: covidwho-2262859
ABSTRACT
COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (Mpro) of SARS-CoV-2 and significantly more potently block the infectivity and replication of various SARS-CoV-2 strains than nirmatrelvir, molnupiravir, and ensitrelvir in cell-based assays employing various target cells. Both compounds also block the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis reveals that both compounds bind to dimer Mpro, apparently promoting Mpro dimerization. X-ray crystallographic analysis shows that both compounds bind to Mpro's active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine of the benzothiazole moiety pointed to solvent. The data suggest that TKB245 and TKB248 might serve as potential therapeutics for COVID-19 and shed light upon further optimization to develop more potent and safer anti-SARS-CoV-2 therapeutics.
Texto completo:
Disponible
Colección:
Bases de datos internacionales
Base de datos:
MEDLINE
Asunto principal:
Antivirales
/
Inhibidores de Proteasas
/
Proteasas 3C de Coronavirus
/
SARS-CoV-2
/
COVID-19
Tipo de estudio:
Estudios diagnósticos
Tópicos:
Variantes
Límite:
Animales
/
Humanos
Idioma:
Inglés
Revista:
Nat Commun
Asunto de la revista:
Biologia
/
Ciencia
Año:
2023
Tipo del documento:
Artículo
País de afiliación:
S41467-023-36729-0
Similares
MEDLINE
...
LILACS
LIS