Azapeptides with unique covalent warheads as SARS-CoV-2 main protease inhibitors.
Antiviral Res
; 225: 105874, 2024 May.
Article
in En
| MEDLINE
| ID: mdl-38555023
ABSTRACT
The main protease (MPro) of SARS-CoV-2, the causative agent of COVID-19, is a pivotal nonstructural protein critical for viral replication and pathogenesis. Its protease function relies on three active site pockets for substrate recognition and a catalytic cysteine for enzymatic activity. To develop potential SARS-CoV-2 antivirals, we successfully synthesized a diverse range of azapeptide inhibitors with various covalent warheads to target MPro's catalytic cysteine. Our characterization identified potent MPro inhibitors, including MPI89 that features an aza-2,2-dichloroacetyl warhead with a remarkable EC50 value of 10 nM against SARS-CoV-2 infection in ACE2+ A549 cells and a selective index of 875. MPI89 is also remarkably selective and shows no potency against SARS-CoV-2 papain-like protease and several human proteases. Crystallography analyses demonstrated that these inhibitors covalently engaged the catalytic cysteine and used the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 stands as one of the most potent MPro inhibitors, suggesting the potential for further exploration of azapeptides and the aza-2,2-dichloroacetyl warhead for developing effective therapeutics against COVID-19.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Coronavirus 3C Proteases
/
SARS-CoV-2
/
COVID-19
Limits:
Humans
Language:
En
Journal:
Antiviral Res
Year:
2024
Document type:
Article
Affiliation country:
United States
Publication country:
HOLANDA
/
HOLLAND
/
NETHERLANDS
/
NL
/
PAISES BAJOS
/
THE NETHERLANDS