Targeting RNA G-quadruplex with repurposed drugs blocks SARS-CoV-2 entry.
Qiyu TongGeng LiuXiongbo SangXinyue ZhuXiaoli FuChao DouYue JianJiani ZhangSailan ZouGuixiang ZhangXiao DuDan LiuShiqian QiWei ChengYan TianXianghui FuPublished in: PLoS pathogens (2023)
The rapid emergence of SARS-CoV-2 variants of concern, the complexity of infection, and the functional redundancy of host factors, underscore an urgent need for broad-spectrum antivirals against the continuous COVID-19 pandemic, with drug repurposing as a viable therapeutic strategy. Here we report the potential of RNA G-quadruplex (RG4)-targeting therapeutic strategy for SARS-CoV-2 entry. Combining bioinformatics, biochemical and biophysical approaches, we characterize the existence of RG4s in several SARS-CoV-2 host factors. In silico screening followed by experimental validation identify Topotecan (TPT) and Berbamine (BBM), two clinical approved drugs, as RG4-stabilizing agents with repurposing potential for COVID-19. Both TPT and BBM can reduce the protein level of RG4-containing host factors, including ACE2, AXL, FURIN, and TMPRSS2. Intriguingly, TPT and BBM block SARS-CoV-2 pseudovirus entry into target cells in vitro and murine tissues in vivo. These findings emphasize the significance of RG4 in SARS-CoV-2 pathogenesis and provide a potential broad-spectrum antiviral strategy for COVID-19 prevention and treatment.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- gene expression
- emergency department
- coronavirus disease
- induced apoptosis
- cancer therapy
- human health
- tyrosine kinase
- climate change
- signaling pathway
- small molecule
- cell proliferation
- oxidative stress
- cell cycle arrest
- molecular dynamics simulations
- drug discovery
- angiotensin converting enzyme
- loop mediated isothermal amplification