Metallodrug Pylorid suppresses SARS-CoV-2 replication and relieves virus-associated pneumonia in Syrian hamsters

Abstract

SARS-CoV-2 leads to a global pandemic of COVID-19 with high infectivity and mortality1. Currently, therapeutic options targeting SARS-CoV-2 are very limited. Metal compounds are historic antimicrobial agents; however, their antiviral activities were barely explored. Here, we screened a set of metallodrugs and related compounds, and identified ranitidine bismuth citrate (Pylorid), a drug in clinical use for the treatment of Helicobacter pylori infection, as a potent anti-SARS-CoV-2 agent both in vitro and in vivo. Pylorid exhibited low cytotoxicity and protected SARS-CoV-2-infected cells. Importantly, it suppressed SARS-CoV-2 replication with decreased viral loads in both upper and lower respiratory tracts, and relieved virus-associated pneumonia in a golden Syrian hamster model. Mechanistic studies revealed that Pylorid and related compounds exhibited excellent inhibition towards both ATPase (IC50=0.69 µM) and DNA-unwinding (IC50 =0.70 µM) activity of SARS-CoV-2 helicase via an irreversible displacement of zinc(II) ions from the enzyme with bismuth(III) ions. Our findings suggest viral helicase as a druggable target and the high clinical potential of bismuth(III) or other metallodrugs for the treatment of SARS-CoV-2 infection.