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Virol Sin ; 35(3): 321-329, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-959357


The ongoing outbreak of Coronavirus Disease 2019 (COVID-19) has become a global public health emergency. SARS-coronavirus-2 (SARS-CoV-2), the causative pathogen of COVID-19, is a positive-sense single-stranded RNA virus belonging to the family Coronaviridae. For RNA viruses, virus-encoded RNA helicases have long been recognized to play pivotal roles during viral life cycles by facilitating the correct folding and replication of viral RNAs. Here, our studies show that SARS-CoV-2-encoded nonstructural protein 13 (nsp13) possesses the nucleoside triphosphate hydrolase (NTPase) and RNA helicase activities that can hydrolyze all types of NTPs and unwind RNA helices dependently of the presence of NTP, and further characterize the biochemical characteristics of these two enzymatic activities associated with SARS-CoV-2 nsp13. Moreover, we found that some bismuth salts could effectively inhibit both the NTPase and RNA helicase activities of SARS-CoV-2 nsp13 in a dose-dependent manner. Thus, our findings demonstrate the NTPase and helicase activities of SARS-CoV-2 nsp13, which may play an important role in SARS-CoV-2 replication and serve as a target for antivirals.

Betacoronavirus/metabolism , Bismuth/pharmacology , Methyltransferases/metabolism , Nucleoside-Triphosphatase/drug effects , RNA Helicases/drug effects , Salts/pharmacology , Viral Nonstructural Proteins/metabolism , Adenosine Triphosphatases/drug effects , Adenosine Triphosphatases/metabolism , Betacoronavirus/enzymology , Betacoronavirus/genetics , COVID-19 , Coronavirus Infections/virology , Humans , Methyltransferases/genetics , Nucleoside-Triphosphatase/genetics , Nucleoside-Triphosphatase/metabolism , Pandemics , Pneumonia, Viral/virology , RNA Helicases/genetics , RNA Helicases/metabolism , Recombinant Proteins , SARS-CoV-2 , Severe Acute Respiratory Syndrome , Viral Nonstructural Proteins/genetics , Virus Replication
Nat Microbiol ; 5(11): 1439-1448, 2020 11.
Article in English | MEDLINE | ID: covidwho-841871


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.

Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Bismuth/pharmacology , Coronavirus Infections/virology , Pneumonia, Viral/virology , Ranitidine/analogs & derivatives , Virus Replication/drug effects , Animals , Betacoronavirus/physiology , COVID-19 , Chemokines/metabolism , Chlorocebus aethiops , Coronavirus Infections/drug therapy , Cytokines/metabolism , Disease Models, Animal , HEK293 Cells , Humans , Lung/pathology , Lung/virology , Mesocricetus , Pandemics , Pneumonia, Viral/drug therapy , RNA Helicases/metabolism , Ranitidine/pharmacology , SARS-CoV-2 , Vero Cells , Viral Load