Back to Search
Start Over
Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2022 Feb 24; Vol. 65 (4), pp. 2905-2925. Date of Electronic Publication: 2021 Jul 09. - Publication Year :
- 2022
-
Abstract
- Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against a broad spectrum of coronaviruses. Described in this Article are novel α-acyloxymethylketone warhead peptidomimetic compounds with a six-membered lactam glutamine mimic in P1. Compounds with potent SARS-CoV-2 3CL protease and in vitro viral replication inhibition were identified with low cytotoxicity and good plasma and glutathione stability. Compounds 15e , 15h , and 15l displayed selectivity for SARS-CoV-2 3CL protease over CatB and CatS and superior in vitro SARS-CoV-2 antiviral replication inhibition compared with the reported peptidomimetic inhibitors with other warheads. The cocrystallization of 15l with SARS-CoV-2 3CL protease confirmed the formation of a covalent adduct. α-Acyloxymethylketone compounds also exhibited antiviral activity against an alphacoronavirus and non-SARS betacoronavirus strains with similar potency and a better selectivity index than remdesivir. These findings demonstrate the potential of the substituted heteroaromatic and aliphatic α-acyloxymethylketone warheads as coronavirus inhibitors, and the described results provide a basis for further optimization.
- Subjects :
- Antiviral Agents chemical synthesis
Antiviral Agents chemistry
COVID-19 metabolism
Coronavirus 3C Proteases metabolism
Cysteine Proteinase Inhibitors chemical synthesis
Cysteine Proteinase Inhibitors chemistry
Glutamine chemistry
Glutamine pharmacology
Humans
Ketones chemistry
Ketones pharmacology
Microbial Sensitivity Tests
Molecular Structure
Peptidomimetics chemistry
SARS-CoV-2 enzymology
Virus Replication drug effects
COVID-19 Drug Treatment
Antiviral Agents pharmacology
Coronavirus 3C Proteases antagonists & inhibitors
Cysteine Proteinase Inhibitors pharmacology
Peptidomimetics pharmacology
SARS-CoV-2 drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 65
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34242027
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c00616