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

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.