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

• Published in: Nature microbiology Vol. 5; no. 11; pp. 1439 - 1448
• Main Authors: Yuan, Shuofeng, Wang, Runming, Chan, Jasper Fuk-Woo, Zhang, Anna Jinxia, Cheng, Tianfan, Chik, Kenn Ka-Heng, Ye, Zi-Wei, Wang, Suyu, Lee, Andrew Chak-Yiu, Jin, Lijian, Li, Hongyan, Jin, Dong-Yan, Yuen, Kwok-Yung, Sun, Hongzhe
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2020; Nature Publishing Group
• Subjects: 631/154; 631/326/22/1295; 631/326/596/4130; Adenosine triphosphatase; Animals; Antimicrobial agents; Antiviral agents; Antiviral Agents - pharmacology; Betacoronavirus - drug effects; Betacoronavirus - physiology; Biomedical and Life Sciences; Bismuth - pharmacology; Chemokines - metabolism; Chlorocebus aethiops; Citric acid; Coronavirus Infections - drug therapy; Coronavirus Infections - virology; Coronaviruses; COVID-19; Cytokines - metabolism; Cytotoxicity; Disease Models, Animal; DNA helicase; HEK293 Cells; Helicobacter pylori; Humans; Infections; Infectious Diseases; Infectivity; Life Sciences; Lung - pathology; Lung - virology; Medical Microbiology; Mesocricetus; Microbiology; Pandemics; Parasitology; Pneumonia; Pneumonia, Viral - drug therapy; Pneumonia, Viral - virology; Ranitidine; Ranitidine - analogs & derivatives; Ranitidine - pharmacology; Ranitidine bismuth citrate; Replication; RNA Helicases - metabolism; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Unwinding; Vero Cells; Viral Load; Virology; Virus Replication - drug effects
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-020-00802-x

SARS-CoV-2 is causing a pandemic of COVID-19, with high infectivity and significant mortality 1 . 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 (IC 50  = 0.69 µM) and DNA-unwinding (IC 50  = 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. Drug used to treat Helicobacter pylori infection reduces SARS-CoV-2 viral loads in lungs and alleviates virus-associated pneumonia in a golden Syrian hamster model.