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Chem Sci ; 13(8): 2238-2248, 2022 Feb 23.
Article in English | MEDLINE | ID: covidwho-1585745


The emergence of SARS-CoV-2 variants of concern compromises vaccine efficacy and emphasizes the need for further development of anti-SARS-CoV-2 therapeutics, in particular orally administered take-home therapies. Cocktail therapy has shown great promise in the treatment of viral infection. Herein, we reported the potent preclinical anti-SARS-CoV-2 efficacy of a cocktail therapy consisting of clinically used drugs, e.g. colloidal bismuth subcitrate (CBS) or bismuth subsalicylate (BSS), and N-acetyl-l-cysteine (NAC). Oral administration of the cocktail reduced viral loads in the lung and ameliorated virus-induced pneumonia in a hamster infection model. The mechanistic studies showed that NAC prevented the hydrolysis of bismuth drugs at gastric pH via the formation of the stable component [Bi(NAC)3], and optimized the pharmacokinetics profile of CBS in vivo. Combination of bismuth drugs with NAC suppressed the replication of a panel of medically important coronaviruses including Middle East respiratory syndrome-related coronavirus (MERS-CoV), Human coronavirus 229E (HCoV-229E) and SARS-CoV-2 Alpha variant (B.1.1.7) with broad-spectrum inhibitory activities towards key viral cysteine enzymes/proteases including papain-like protease (PLpro), main protease (Mpro), helicase (Hel) and angiotensin-converting enzyme 2 (ACE2). Importantly, our study offered a potential at-home treatment for combating SARS-CoV-2 and future coronavirus infections.

Nature ; 593(7859): 418-423, 2021 05.
Article in English | MEDLINE | ID: covidwho-1137788


The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.

Antiviral Agents/pharmacology , Clofazimine/pharmacology , Coronavirus/classification , Coronavirus/drug effects , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Biological Availability , Cell Fusion , Cell Line , Clofazimine/pharmacokinetics , Clofazimine/therapeutic use , Coronavirus/growth & development , Coronavirus/pathogenicity , Cricetinae , DNA Helicases/antagonists & inhibitors , Drug Synergism , Female , Humans , Life Cycle Stages/drug effects , Male , Mesocricetus , Pre-Exposure Prophylaxis , SARS-CoV-2/growth & development , Species Specificity , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Transcription, Genetic/drug effects , Transcription, Genetic/genetics
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