2. Academic Validation
  3. Targeting RNA G-quadruplex with repurposed drugs blocks SARS-CoV-2 entry

Targeting RNA G-quadruplex with repurposed drugs blocks SARS-CoV-2 entry

  • PLoS Pathog. 2023 Jan 26;19(1):e1011131. doi: 10.1371/journal.ppat.1011131.
Qiyu Tong 1,  Geng Liu 1,  Xiongbo Sang 1,  Xinyue Zhu 1,  Xiaoli Fu 2,  Chao Dou 3,  Yue Jian 1,  Jiani Zhang 1,  Sailan Zou 1,  Guixiang Zhang 3,  Xiao Du 3,  Dan Liu 4,  Shiqian Qi 5,  Wei Cheng 2,  Yan Tian 1,  Xianghui Fu 1
Affiliations

Affiliations

  • 1 Division of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China.
  • 2 Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 3 Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 4 Division of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 5 Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
PMID: 36701392 DOI: 10.1371/journal.ppat.1011131
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.

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