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Insights into SARS-CoV-2 replication control via targeting the host hijacking function of NSP12
Shirui Fan1,2, Xinyan Long3, Wei Zheng1
1State Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
Acta Pharmaceutica Sinica. B
|July 15, 2026
Summary
SARS-CoV-2 NSP12 hijacks host Hsc70 chaperone for stability. This interaction balances degradation and accumulation, enhancing viral replication. A new antiviral, Hlyc41, disrupts this mechanism, promoting NSP12 degradation and suppressing the virus.
Area of Science:
- Virology
- Molecular Biology
- Cellular Biology
Background:
- SARS-CoV-2 nonstructural protein 12 (NSP12) is the RNA-dependent RNA polymerase (RdRp) essential for viral RNA synthesis.
- Precise regulation of NSP12 levels is critical for efficient viral replication, but the underlying mechanisms are poorly understood.
Purpose of the Study:
- To elucidate the mechanisms governing SARS-CoV-2 NSP12 stability.
- To identify host factors involved in regulating NSP12 levels.
- To explore potential therapeutic strategies targeting NSP12 stability.
Main Methods:
- Investigated the interaction between SARS-CoV-2 NSP12 and host chaperone Hsc70.
- Utilized chaperone-mediated autophagy (CMA) assays to assess NSP12 degradation.
- Analyzed the effect of Hlyc41 on Hsc70-NSP12 binding and viral replication.
Main Results:
- SARS-CoV-2 NSP12 hijacks Hsc70, which plays a dual role in NSP12 degradation via CMA and accumulation.
- NSP12 evades CMA by binding Hsc70 with high affinity, disrupting Hsc70-LAMP2a interaction and promoting accumulation.
- The antiviral Hlyc41 disrupts NSP12-Hsc70 binding at residue F428, enhancing NSP12 degradation and suppressing viral replication.
Conclusions:
- A novel host hijacking mechanism regulates SARS-CoV-2 NSP12 stability through Hsc70.
- The balance between Hsc70-mediated degradation and accumulation dictates NSP12 fate.
- Targeting the NSP12-Hsc70 interaction with agents like Hlyc41 presents a promising antiviral strategy.
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