SARS-CoV-2 main protease inhibition through dimerization promotion by peptidomimetic inhibitors and disruption by ebselen
et al., eLife, doi:10.7554/elife.109956, Oct 2026
In vitro study investigating how peptidomimetic inhibitors and non-peptidomimetic inhibitors affect SARS-CoV-2 main protease (Mpro) dimerization and conformational dynamics.
Liu et al., 26 Oct 2026, peer-reviewed, 4 authors.
Contact: zhongping.yao@polyu.edu.hk.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract:
*For correspondence: zhongping.yao@polyu.edu.hk
† These authors contributed equally to this work
Competing interest: The authors declare that no competing interests exist.
Funding: See page 17
Preprint posted
16 December 2025 Sent for Review 17 November 2025 Reviewed preprint v1 17 February 2026 Reviewed preprint v2 11 September 2026 Reviewed preprint v3 18 September 2026 Version of Record 26 October 2026
Reviewing Editor: Chang Liu, Johns Hopkins University, United States
Copyright Liu, Jia, Zhao et al . This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
SARS- CoV- 2 main protease inhibition through dimerization promotion by peptidomimetic inhibitors and disruption by ebselen
Chengxi Liu 1,2† , Qinyu Jia 1,2† , Chang Zhao 1,2† , Zhong- Ping Yao 1,2 *
1 Department of Life Sciences, Food Safety and Technology Research Centre, and Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong, China; 2 State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), and Shenzhen Key Laboratory of Food Biological Safety Control, Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
eLife Assessment
This important study compares how different classes of drugs act on the SARS- CoV- 2 main protease, a key antiviral target, and shows that many of them work by controlling whether the enzyme assembles into its active dimeric form. The evidence, based on a range of complementary biophysical methods, is convincing and points to the interface between the two protein protomers, including a newly found binding site, as a promising target for broad- spectrum antiviral drugs. This work will be of interest to biochemists and virologists working on treatments for coronaviruses.
Abstract The SARS- CoV- 2 main protease (M pro ) is a key antiviral target that equilibrates between an active dimer and inactive monomer, making the dimerization interface a promising therapeutic vulnerability. This study investigates M pro monomer- dimer equilibrium and conformational changes induced by inhibitor binding using 13 C labeling with native mass spectrometry and hydrogen/ deuterium exchange mass spectrometry (HDX- MS). We evaluated how peptidomimetic inhibitors (PF- 07321332, PF- 00835231, GC376, boceprevir) and non- peptidomimetic inhibitors (carmofur, ebselen, MR6- 31- 2, AT7519, pelitinib) influence M pro dimerization and subunit exchange. Key findings revealed divergent mechanisms: peptidomimetic inhibitors significantly shifted the equilibrium towards the dimeric state, suppressing subunit exchange dynamics and rigidifying the dimer interface; in contrast, ebselen impaired dimer formation and increased interface flexibility. Notably, tandem mass spectrometry identified a novel covalent binding site for ebselen at C300. Molecular dynamics simulations and mutational analyses demonstrated that this C300 modification allosterically alters the hydrogen bond network of the dimer interface, directly contributing to ebselenmediated dimer disruption and enzymatic inhibition. Overall, this study clarifies distinct inhibitory modes between peptidomimetics and ebselen, highlighting the therapeutic potential of targeting allosteric sites at the dimer interface for designing next- generation M pro..
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"abstract": "<jats:p>\n The SARS-CoV-2 main protease (M\n <jats:sup>pro</jats:sup>\n ) is a key antiviral target that equilibrates between an active dimer and inactive monomer, making the dimerization interface a promising therapeutic vulnerability. This study investigates M\n <jats:sup>pro</jats:sup>\n monomer-dimer equilibrium and conformational changes induced by inhibitor binding using\n <jats:sup>13</jats:sup>\n C labeling with native mass spectrometry and hydrogen/deuterium exchange mass spectrometry (HDX-MS). We evaluated how peptidomimetic inhibitors (PF-07321332, PF-00835231, GC376, boceprevir) and non-peptidomimetic inhibitors (carmofur, ebselen, MR6-31-2, AT7519, pelitinib) influence M\n <jats:sup>pro</jats:sup>\n dimerization and subunit exchange. Key findings revealed divergent mechanisms: peptidomimetic inhibitors significantly shifted the equilibrium towards the dimeric state, suppressing subunit exchange dynamics and rigidifying the dimer interface; in contrast, ebselen impaired dimer formation and increased interface flexibility. Notably, tandem mass spectrometry identified a novel covalent binding site for ebselen at C300. Molecular dynamics simulations and mutational analyses demonstrated that this C300 modification allosterically alters the hydrogen bond network of the dimer interface, directly contributing to ebselen-mediated dimer disruption and enzymatic inhibition. Overall, this study clarifies distinct inhibitory modes between peptidomimetics and ebselen, highlighting the therapeutic potential of targeting allosteric sites at the dimer interface for designing next-generation M\n <jats:sup>pro</jats:sup>\n inhibitors.\n </jats:p>",
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