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- Title
Targeting RNA G-quadruplex with repurposed drugs blocks SARS-CoV-2 entry.
- Authors
Tong, Qiyu; Liu, Geng; Sang, Xiongbo; Zhu, Xinyue; Fu, Xiaoli; Dou, Chao; Jian, Yue; Zhang, Jiani; Zou, Sailan; Zhang, Guixiang; Du, Xiao; Liu, Dan; Qi, Shiqian; Cheng, Wei; Tian, Yan; Fu, Xianghui
- Abstract
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. Author summary: 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 novel broad-spectrum antiviral strategies. RNA G-quadruplex (RG4), a non-canonical RNA secondary structure, has been recently implicated in the regulation of SARS-CoV-2 and host factors. Here, we further characterize the existence and functional importance of RG4s in several host factors, including ACE2. Moreover, we identify that Topotecan and Berbamine, two approved drugs, can function as RG4-stabilizing agents to repress RG4-containing host factors and protect cells and mice against SARS-CoV-2 pseudovirus entry. Together, this work highlights the significance of RG4 in SARS-CoV-2 pathogenesis and provide an attractive broad-spectrum antiviral strategy for COVID-19 prevention and control.
- Subjects
SARS-CoV-2; COVID-19 treatment; RNA; DRUG repositioning; QUADRUPLEX nucleic acids; COVID-19 pandemic
- Publication
PLoS Pathogens, 2023, Vol 18, Issue 1, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1011131