Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CLpro).
J Med Chem
; 65(4): 2880-2904, 2022 02 24.
Artículo
en Inglés
| MEDLINE | ID: covidwho-1705973
ABSTRACT
Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.
Texto completo:
Disponible
Colección:
Bases de datos internacionales
Base de datos:
MEDLINE
Asunto principal:
Antivirales
/
Inhibidores de Cisteína Proteinasa
/
Peptidomiméticos
/
Proteasas 3C de Coronavirus
/
SARS-CoV-2
Límite:
Animales
/
Humanos
Idioma:
Inglés
Revista:
J Med Chem
Asunto de la revista:
Química
Año:
2022
Tipo del documento:
Artículo
País de afiliación:
Acs.jmedchem.1c00598
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