9pjf
GII.4 Human Norovirus 3CL protease bound to compound 27
Structural highlights
FunctionK4L8Z7_9CALI 3C-like protease processes the polyprotein: 3CLpro-RdRp is first released by autocleavage, then all other proteins are cleaved. May cleave polyadenylate-binding protein thereby inhibiting cellular translation.[PROSITE-ProRule:PRU00870] Publication Abstract from PubMedThe cysteine 3C-like proteases (3CL(pro)) 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 3CL(pro) of caliciviruses (NS6), coronaviruses (M(pro)), 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). Broad-Spectrum Peptidomimetic Inhibitors of Norovirus and Coronavirus 3C-like Proteases.,Brimble MA, Stubbing LA, Hermant YO, Yang SH, Hubert JG, Pearl ES, McSweeney AM, Young VL, Campbell AC, Opel-Reading HK, McKenzie-Goldsmith GM, Putha L, Mortuza R, Wang H, Hurst BL, Julander J, Harris LD, Krause KL, Ward VK ACS Infect Dis. 2025 Dec 18. doi: 10.1021/acsinfecdis.5c00680. PMID:41412823[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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