Atazanavir, Alone or in Combination with Ritonavir, Inhibits SARS-CoV-2 Replication and Proinflammatory Cytokine Production

Antimicrob Agents Chemother. 2020 Sep 21;64(10):e00825-20. doi: 10.1128/AAC.00825-20. Print 2020 Sep 21.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors. Extensive use of atazanavir (ATV) as antiretroviral and previous evidence suggesting its bioavailability within the respiratory tract prompted us to study this molecule against SARS-CoV-2. Our results show that ATV docks in the active site of SARS-CoV-2 Mpro with greater strength than LPV, blocking Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells and a human pulmonary epithelial cell line. ATV/RTV also impaired virus-induced enhancement of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.

Keywords: COVID-19; SARS-CoV-2; antiviral; atazanavir; coronavirus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Atazanavir Sulfate / chemistry
  • Atazanavir Sulfate / pharmacology*
  • Betacoronavirus / drug effects*
  • Betacoronavirus / pathogenicity
  • Betacoronavirus / physiology
  • COVID-19
  • COVID-19 Drug Treatment
  • Cell Death / drug effects
  • Chlorocebus aethiops
  • Coronavirus 3C Proteases
  • Coronavirus Infections / drug therapy
  • Coronavirus Infections / metabolism
  • Coronavirus Infections / pathology
  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / metabolism
  • Cytokines / metabolism*
  • Drug Therapy, Combination
  • Humans
  • Inflammation / metabolism
  • Inflammation / virology
  • Lopinavir / pharmacology
  • Molecular Docking Simulation
  • Monocytes / virology
  • Pandemics
  • Pneumonia, Viral / drug therapy
  • Pneumonia, Viral / metabolism
  • Pneumonia, Viral / pathology
  • Protease Inhibitors / pharmacology
  • Ritonavir / pharmacology*
  • SARS-CoV-2
  • Vero Cells
  • Viral Nonstructural Proteins / antagonists & inhibitors
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Cytokines
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • Lopinavir
  • Atazanavir Sulfate
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases
  • Ritonavir