ACS infectious diseases · 2025
Broad-Spectrum Peptidomimetic Inhibitors of Norovirus and Coronavirus 3C-like Proteases.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Brimble Margaret A, Stubbing Louise A, Hermant Yann O, Yang Sung-Hyun, Hubert Jonathan G, Pearl Esperanza S, McSweeney Alice M, Young Vivienne L, Campbell Ashley C, Opel-Reading Helen K, McKenzie-Goldsmith Geena M, Putha Lohitha, Mortuza Roman, Wang Hong, Hurst Brett L, Julander Justin, Harris Lawrence D, Krause Kurt L, Ward Vernon K
Аннотация
The cysteine 3C-like proteases (3CLpro) of caliciviruses, coronaviruses, and picornaviruses are essential for viral replication. In this study, we report the development of potent broad-spectrum peptidomimetic antiviral agents that target the 3CLpro of caliciviruses (NS6), coronaviruses (Mpro), and a picornavirus (3C). Based upon previously reported inhibitors, a small library of compounds was designed, synthesized and tested to identify a core structure, which was then derivatized with a focus upon P3 and P4 positions to afford new inhibitors with improved potency against the respective viral enzymes and enhanced binding as determined by X-ray crystallography. These compounds were tested against a range of viruses in culture, revealing minimal toxicity while exhibiting broad-spectrum potent nanomolar activities against noroviruses and several coronavirus species, including alpha and omicron variants of SARS-CoV-2 and Middle East Respiratory Syndrome virus (MERS).