Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 4, Pages 2905-2925Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00616
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Funding
- Alberta Innovates [RES27408]
- Canadian Institutes of Health Research Rapid Research [VR3-172655]
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This study describes novel antiviral compounds against coronaviruses, which have good activity and stability, and show effective inhibition of SARS-CoV-2 replication. They also exhibit better selectivity index and broad-spectrum antiviral activity against different types of coronaviruses.
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 alpha-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 151 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 151 with SARSCoV-2 3CL protease confirmed the formation of a covalent adduct. alpha-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 alpha-acyloxymethylketone warheads as coronavirus inhibitors, and the described results provide a basis for further optimization.
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