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Arsenic trioxide could promote SARS-CoV-2 NSP12 protein degradation

Tao Yang1,2, Chen Ying Zhu1, Pei Han Yu1

  • 1Department of Public Health, Zhejiang University School of Medicine, Hangzhou, 310058, PR China.

The Journal of General Virology
|July 7, 2025
PubMed

Insights

Arsenic trioxide (ATO) effectively reduces SARS-CoV-2 NSP12, including variants, by promoting its degradation. This offers a potential new therapeutic strategy against SARS-CoV-2 replication.

Area of Science:

  • Virology
  • Drug Discovery
  • Molecular Biology

Background:

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants challenge vaccine efficacy.
  • Non-structural protein 12 (NSP12), the viral RNA-dependent RNA polymerase, is crucial for SARS-CoV-2 replication and a key drug target.
  • Existing NSP12 inhibitors show reduced efficacy against drug-resistant SARS-CoV-2 variants.

Purpose of the Study:

  • To identify novel therapeutic agents targeting SARS-CoV-2 replication.
  • To investigate the effect of arsenic trioxide (ATO) on SARS-CoV-2 NSP12.
  • To elucidate the mechanism of ATO-induced NSP12 reduction.

Main Methods:

  • Assessed the impact of ATO on wild-type (WT) and mutant SARS-CoV-2 NSP12 levels.
  • Investigated the role of the ubiquitin-proteasome pathway in NSP12 degradation.
  • Identified the specific E3 ligase responsible for ATO-mediated NSP12 ubiquitination.

Main Results:

  • Arsenic trioxide (ATO) significantly reduced both WT and mutant SARS-CoV-2 NSP12 levels with low toxicity.
  • ATO treatment induced robust ubiquitination and subsequent proteasomal degradation of NSP12.
  • STIP1 homology and U-box containing protein 1 was identified as the E3 ligase mediating this process.

Conclusions:

  • ATO presents a potential therapeutic intervention against SARS-CoV-2 by targeting NSP12 degradation.
  • This mechanism offers a strategy to overcome drug resistance in SARS-CoV-2 variants.
  • ATO's action broadens its potential therapeutic applications for viral infections.
Keywords:
arsenic trioxidedegradationnon-structural protein 12severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

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