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Disulfide bond formation between Cys22 and Cys44 in SARS-CoV-2 main protease.
Lauren R Blankenship1, Kai Yang1, Chia-Chuan Dean Cho1
1Texas A&M Drug Discovery Center and Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
Bioorganic & Medicinal Chemistry Letters
|May 26, 2026
Summary
SARS-CoV-2 main protease (MPro) undergoes redox modifications, including novel Cys22-Cys44 disulfide formation. These modifications suggest potential redox regulation of MPro activity during viral infection.
Area of Science:
- Biochemistry
- Structural Biology
- Virology
Background:
- SARS-CoV-2 main protease (MPro) is a critical enzyme for viral replication.
- MPro possesses multiple cysteine residues susceptible to covalent modifications.
- Previous studies reported various modifications, including disulfide bonds and crosslinks.
Purpose of the Study:
- To investigate novel redox modifications of SARS-CoV-2 MPro.
- To explore the structural and functional implications of these modifications.
- To assess the potential role of redox regulation in MPro activity.
Main Methods:
- Reanalysis of existing MPro crystal structures.
- Determination of new MPro crystal structures.
- Biochemical assays using wild-type and mutant MPro enzymes.
Main Results:
- Identification of nine structures with S-O-N (SON) crosslinks and thirty-one with S-O-N-O-S (SONOS) crosslinks.
- Discovery of a novel Cys22-Cys44 disulfide bond in a newly determined structure.
- A C22S mutant enzyme exhibited significantly higher activity than wild-type MPro.
Conclusions:
- Redox transformations involving Cys22 and Cys44 suggest potential redox regulation of MPro.
- These modifications may influence MPro activity in host cells experiencing oxidative stress.
- The findings support a role for redox mechanisms in controlling MPro function.
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