SARS-CoV-2 Ana Proteazının Peptidomimetik İnhibitörlerle Dimerleşme Teşviki ve Ebselen ile Bozunması Yoluyla İnhibisyonu

Özet (abstract)

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 form 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 pro inhibitors.

Yazarların özeti; kaynağından alınmıştır. eLife, 2026 · DOI ↗