An orally available Mpro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron.
Nat Microbiol
; 7(5): 716-725, 2022 05.
Article
de En
| MEDLINE
| ID: mdl-35477751
ABSTRACT
Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (Mpro) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants. We herein report a series of potent α-ketoamide-containing Mpro inhibitors obtained using the Ugi four-component reaction. The prioritized compound, Y180, showed an IC50 of 8.1 nM against SARS-CoV-2 Mpro and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively. Y180 protected against wild-type SARS-CoV-2, B.1.1.7 (Alpha), B.1.617.1 (Kappa) and P.3 (Theta), with EC50 of 11.4, 20.3, 34.4 and 23.7 nM, respectively. Oral treatment with Y180 displayed a remarkable antiviral potency and substantially ameliorated the virus-induced tissue damage in both nasal turbinate and lung of B.1.1.7-infected K18-human ACE2 (K18-hACE2) transgenic mice. Therapeutic treatment with Y180 improved the survival of mice from 0 to 44.4% (P = 0.0086) upon B.1.617.1 infection in the lethal infection model. Importantly, Y180 was also highly effective against the B.1.1.529 (Omicron) variant both in vitro and in vivo. Overall, our study provides a promising lead compound for oral drug development against SARS-CoV-2.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
SARS-CoV-2
/
Traitements médicamenteux de la COVID-19
Limites:
Animals
/
Humans
Langue:
En
Journal:
Nat Microbiol
Année:
2022
Type de document:
Article
Pays d'affiliation:
Chine