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Production of Human Norovirus Protruding Domains in E. coli for X-ray Crystallography
Published on: April 19, 2016
Broad-Spectrum Peptidomimetic Inhibitors of Norovirus and Coronavirus 3C-like Proteases
Margaret A Brimble1,2, Louise A Stubbing1,2, Yann O Hermant1,2
1School of Chemical Sciences, School of Biological Sciences, The University of Auckland, 23 Symonds Street, 3b Symonds Street, Auckland 1142, New Zealand.
Abstract:
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).
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