Atazanavir, Alone or in Combination with Ritonavir, Inhibits SARS-CoV-2 Replication and Proinflammatory Cytokine Production.
Animals
Antiviral Agents
/ pharmacology
Atazanavir Sulfate
/ chemistry
Betacoronavirus
/ drug effects
COVID-19
Cell Death
/ drug effects
Chlorocebus aethiops
Coronavirus 3C Proteases
Coronavirus Infections
/ drug therapy
Cysteine Endopeptidases
/ chemistry
Cytokines
/ metabolism
Drug Therapy, Combination
Humans
Inflammation
/ metabolism
Lopinavir
/ pharmacology
Molecular Docking Simulation
Monocytes
/ virology
Pandemics
Pneumonia, Viral
/ drug therapy
Protease Inhibitors
/ pharmacology
Ritonavir
/ pharmacology
SARS-CoV-2
Vero Cells
Viral Nonstructural Proteins
/ antagonists & inhibitors
Virus Replication
/ drug effects
COVID-19 Drug Treatment
COVID-19
SARS-CoV-2
antiviral
atazanavir
coronavirus
Journal
Antimicrobial agents and chemotherapy
ISSN: 1098-6596
Titre abrégé: Antimicrob Agents Chemother
Pays: United States
ID NLM: 0315061
Informations de publication
Date de publication:
21 09 2020
21 09 2020
Historique:
received:
28
04
2020
accepted:
02
08
2020
pubmed:
8
8
2020
medline:
2
10
2020
entrez:
8
8
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32759267
pii: AAC.00825-20
doi: 10.1128/AAC.00825-20
pmc: PMC7508582
pii:
doi:
Substances chimiques
Antiviral Agents
0
Cytokines
0
Protease Inhibitors
0
Viral Nonstructural Proteins
0
Lopinavir
2494G1JF75
Atazanavir Sulfate
4MT4VIE29P
Cysteine Endopeptidases
EC 3.4.22.-
Coronavirus 3C Proteases
EC 3.4.22.28
Ritonavir
O3J8G9O825
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2020 American Society for Microbiology.
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