2. Academic Validation
  3. Metallodrug ranitidine bismuth citrate suppresses SARS-CoV-2 replication and relieves virus-associated pneumonia in Syrian hamsters

Metallodrug ranitidine bismuth citrate suppresses SARS-CoV-2 replication and relieves virus-associated pneumonia in Syrian hamsters

  • Nat Microbiol. 2020 Nov;5(11):1439-1448. doi: 10.1038/s41564-020-00802-x.
Shuofeng Yuan  # 1,  Runming Wang  # 2,  Jasper Fuk-Woo Chan  # 1 3,  Anna Jinxia Zhang 1,  Tianfan Cheng 4,  Kenn Ka-Heng Chik 1,  Zi-Wei Ye 1,  Suyu Wang 2,  Andrew Chak-Yiu Lee 1,  Lijian Jin 4,  Hongyan Li 2,  Dong-Yan Jin 5,  Kwok-Yung Yuen 6 7,  Hongzhe Sun 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, Hong Kong, China.
  • 2 Department of Chemistry, State Key Laboratory of Synthetic Chemistry, CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, Hong Kong, China.
  • 3 Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China.
  • 4 Faculty of Dentistry, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, Hong Kong, China.
  • 5 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, Hong Kong, China.
  • 6 State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, Hong Kong, China. kyyuen@hku.hk.
  • 7 Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China. kyyuen@hku.hk.
  • 8 Department of Chemistry, State Key Laboratory of Synthetic Chemistry, CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, Hong Kong, China. hsun@hku.hk.
  • # Contributed equally.
PMID: 33028965 DOI: 10.1038/s41564-020-00802-x
Abstract

SARS-CoV-2 is causing a pandemic of COVID-19, with high infectivity and significant mortality1. Currently, therapeutic options for COVID-19 are limited. Historically, metal compounds have found use as antimicrobial agents, but their Antiviral activities have rarely been explored. Here, we test a set of metallodrugs and related compounds, and identify ranitidine bismuth citrate, a commonly used drug for the treatment of Helicobacter pylori Infection, as a potent anti-SARS-CoV-2 agent, both in vitro and in vivo. Ranitidine bismuth citrate exhibited low cytotoxicity and protected SARS-CoV-2-infected cells with a high selectivity index of 975. Importantly, ranitidine bismuth citrate suppressed SARS-CoV-2 replication, leading to decreased viral loads in both upper and lower respiratory tracts, and relieved virus-associated pneumonia in a golden Syrian hamster model. In vitro studies showed that ranitidine bismuth citrate and its related compounds exhibited inhibition towards both the ATPase (IC50 = 0.69 µM) and DNA-unwinding (IC50 = 0.70 µM) activities of the SARS-CoV-2 helicase via an irreversible displacement of zinc(II) ions from the Enzyme by bismuth(III) ions. Our findings highlight viral helicase as a druggable target and the clinical potential of bismuth(III) drugs or Other metallodrugs for the treatment of SARS-CoV-2 Infection.

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