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
| Autor: | Muhammad Bashir Khan, Jimmy Lu, Elena Arutyunova, John C. Vederas, James A. Nieman, Howard S. Young, Mohammad Rahim, Yanhua Du, Wayne Vuong, M. Joanne Lemieux, Marco J. van Belkum, Holly A. Saffran, Conrad Fischer, Bing Bai, Alexandr Belovodskiy, Michael A. Joyce, Fusen Lin, Jia Xu, Hena Mostafa, Justin Shields, Darren Hockman, Tess Lamer, D. Lorne Tyrrell, Appan Srinivas Kandadai, Sardeev K Bajwa, Zhengxian Gu |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Protease 010405 organic chemistry Peptidomimetic viruses medicine.medical_treatment medicine.disease_cause 01 natural sciences In vitro 3. Good health 0104 chemical sciences Glutamine 03 medical and health sciences chemistry.chemical_compound Biochemistry chemistry Viral replication Drug Discovery medicine Lactam Molecular Medicine Cytotoxicity 030304 developmental biology Coronavirus |
| Zdroj: | Journal of Medicinal Chemistry. 65:2905-2925 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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