Targeting the Ero1α-PDI oxidative protein folding pathway as a broad-spectrum strategy against coronavirus.
4 affiliations
- 1State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
- 2State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- 3State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected].
- 4State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected].
Abstract
The rapid mutation of the SARS-CoV-2 spike (S) protein promotes immune evasion and challenges current therapeutics. However, its cysteine/disulfide bond pattern is highly conserved across coronaviruses and essential for its structure and function. Here, we demonstrate that the folding and maturation of the S protein is a redox-sensitive process managed by sulfhydryl oxidase Ero1α and protein disulfide isomerase (PDI) in the endoplasmic reticulum. Reducing agents or cysteine mutations inhibit furin-processing of the S protein and its transport to the plasma membrane. Genetic or pharmacological disruption of the Ero1α-PDI pathway impairs S protein oxidative folding, furin cleavage and plasma membrane localization, as well as its fusogenic activity. Using a SARS-CoV-2 reverse genetics model, we confirm that targeting the Ero1α-PDI pathway exhibits potent antiviral effect. Moreover, the Ero1α-PDI pathway is essential for S protein maturation across different β-coronaviruses. Thus, our findings highlight the oxidative protein folding machinery as a promising target for developing broad-spectrum anti-coronavirus therapies.
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BibTeX
@article{li2026targeting,
title = {{Targeting the Ero1α-PDI oxidative protein folding pathway as a broad-spectrum strategy against coronavirus.}},
author = {Xinqian Li and Ping Liu and Xi'e Wang and Xi Wang and Lei Wang},
journal = {Redox biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104427},
url = {https://europepmc.org/article/MED/42843276},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Targeting the Ero1α-PDI oxidative protein folding pathway as a broad-spectrum strategy against coronavirus.
AU - Xinqian Li
AU - Ping Liu
AU - Xi'e Wang
AU - Xi Wang
AU - Lei Wang
PY - 2026
DA - 2026/10/05
JO - Redox biology
DO - 10.1016/j.redox.2026.104427
UR - https://europepmc.org/article/MED/42843276
AB - The rapid mutation of the SARS-CoV-2 spike (S) protein promotes immune evasion and challenges current therapeutics. However, its cysteine/disulfide bond pattern is highly conserved across coronaviruses and essential for its structure and function. Here, we demonstrate that the folding and maturation of the S protein is a redox-sensitive process managed by sulfhydryl oxidase Ero1α and protein disulfide isomerase (PDI) in the endoplasmic reticulum. Reducing agents or cysteine mutations inhibit furin-processing of the S protein and its transport to the plasma membrane. Genetic or pharmacological disruption of the Ero1α-PDI pathway impairs S protein oxidative folding, furin cleavage and plasma membrane localization, as well as its fusogenic activity. Using a SARS-CoV-2 reverse genetics model, we confirm that targeting the Ero1α-PDI pathway exhibits potent antiviral effect. Moreover, the Ero1α-PDI pathway is essential for S protein maturation across different β-coronaviruses. Thus, our findings highlight the oxidative protein folding machinery as a promising target for developing broad-spectrum anti-coronavirus therapies.
SN - 2213-2317
ER -