SARS-CoV-2 main protease inhibition through dimerization promotion by peptidomimetic inhibitors and disruption by ebselen.
- 1Department of Life Sciences, Food Safety and Technology Research Centre, and Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong, China.
- 2State 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.
Abstract
The SARS-CoV-2 main protease (Mpro) 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 Mpro monomer-dimer equilibrium and conformational changes induced by inhibitor binding using ¹³C 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 Mpro 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 Mpro inhibitors.
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BibTeX
@article{liu2026sarscov2,
title = {{SARS-CoV-2 main protease inhibition through dimerization promotion by peptidomimetic inhibitors and disruption by ebselen.}},
author = {Chengxi Liu and Qinyu Jia and Chang Zhao and Zhong-Ping Yao},
journal = {ELife},
year = {2026},
month = oct,
doi = {10.7554/elife.109956},
url = {https://europepmc.org/article/MED/42930075},
note = {CC BY},
}
RIS
TY - JOUR
TI - SARS-CoV-2 main protease inhibition through dimerization promotion by peptidomimetic inhibitors and disruption by ebselen.
AU - Chengxi Liu
AU - Qinyu Jia
AU - Chang Zhao
AU - Zhong-Ping Yao
PY - 2026
DA - 2026/10/26
JO - ELife
DO - 10.7554/elife.109956
UR - https://europepmc.org/article/MED/42930075
AB - The SARS-CoV-2 main protease (Mpro) 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 Mpro monomer-dimer equilibrium and conformational changes induced by inhibitor binding using ¹³C 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 Mpro 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 Mpro inhibitors.
SN - 2050-084X
ER -