Broad-Spectrum Peptidomimetic Inhibitors of Norovirus and Coronavirus 3C-like Proteases

The cysteine 3C-like proteases (3CL<sup>pro</sup>) 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<sup>pro</sup> of caliciviruses (NS6), coronaviruses (M<sup>pro</sup>), 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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Publication Details

Journal
ACS Infectious Diseases
Published
2025-12-18
DOI
https://doi.org/10.1021/acsinfecdis.5c00680
Primary Topic
Viral gastroenteritis research and epidemiology
Type
article
Field-Weighted Citation Impact
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article

Broad-Spectrum Peptidomimetic Inhibitors of Norovirus and Coronavirus 3C-like Proteases

Lohitha Putha, Geena M. McKenzie-Goldsmith, Vivienne L. Young, Esperanza S. Pearl et al.
ACS Infectious Diseases
Viral gastroenteritis research and epidemiology
article

Broad-Spectrum Peptidomimetic Inhibitors of Norovirus and Coronavirus 3C-like Proteases

Lohitha Putha, Geena M. McKenzie-Goldsmith, Vivienne L. Young, Esperanza S. Pearl, Kurt L. Krause, Brett L. Hurst, Justin G. Julander, Roman Mortuza, Margaret Anne Brimble, Alice M. McSweeney, Helen K. Opel‐Reading, Yann O. Hermant, Louise A. Stubbing, Lawrence D. Harris, Vernon K. Ward, A.C. Campbell, Jonathan G. Hubert, Hong Wang, Sung-Hyun Yang
article en

Abstract

The cysteine 3C-like proteases (3CL<sup>pro</sup>) 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<sup>pro</sup> of caliciviruses (NS6), coronaviruses (M<sup>pro</sup>), 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).

ACS Infectious DiseasesVol. 12(1)
Utah State University (US), University of Auckland (NZ), Victoria University of Wellington (NZ), Maurice Wilkins Centre (NZ), University of Otago (NZ)
Openalex Percentile: Top 52%
Viral gastroenteritis research and epidemiology
DOISourceOpenAlex
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