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Antimicrobial agents and chemotherapy
05 21, 2020;64 (6):

MK-571, a Cysteinyl Leukotriene Receptor 1 Antagonist, Inhibits Hepatitis C Virus Replication.

Isaac Ruiz, Quentin Nevers, Eva Hernández, Nazim Ahnou, Rozenn Brillet, Laurent Softic, Flora Donati, Francois Berry, Sabah Hamadat, Slim Fourati, Jean-Michel Pawlotsky, Abdelhakim Ahmed-Belkacem
Author Information
  1. Isaac Ruiz: Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
  2. Quentin Nevers: Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
  3. Eva Hernández: Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
  4. Nazim Ahnou: Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
  5. Rozenn Brillet: Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
  6. Laurent Softic: Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
  7. Flora Donati: Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
  8. Francois Berry: Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
  9. Sabah Hamadat: Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
  10. Slim Fourati: Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France. ORCID
  11. Jean-Michel Pawlotsky: Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
  12. Abdelhakim Ahmed-Belkacem: Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France hakim.ahmed-belkacem@inserm.fr. ORCID
PMID: 32179525 DOI: 10.1128/AAC.02078-19

Abstract

The quinoline MK-571 is the most commonly used inhibitor of multidrug resistance protein-1 (MRP-1) but was originally developed as a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist. While studying the modulatory effect of MRP-1 on anti-hepatitis C virus (HCV) direct-acting antiviral (DAA) efficiency, we observed an unexpected anti-HCV effect of compound MK-571 alone. This anti-HCV activity was characterized in Huh7.5 cells stably harboring a subgenomic genotype 1b replicon. A dose-dependent decrease of HCV RNA levels was observed upon MK-571 administration, with a 50% effective concentration (EC ± standard deviation) of 9 ± 0.3 μM and a maximum HCV RNA level reduction of approximatively 1 log MK-571 also reduced the replication of the HCV full-length J6/JFH1 model in a dose-dependent manner. However, probenecid and apigenin homodimer (APN), two specific inhibitors of MRP-1, had no effect on HCV replication. In contrast, the CysLTR1 antagonist SR2640 increased HCV-subgenomic replicon (SGR) RNA levels in a dose-dependent manner, with a maximum increase of 10-fold. In addition, a combination of natural CysLTR1 agonist (LTD4) or antagonists (zafirlukast, cinalukast, and SR2640) with MK-571 completely reversed its antiviral effect, suggesting its anti-HCV activity is related to CysLTR1 rather to MRP-1 inhibition. In conclusion, we showed that MK-571 inhibits HCV replication in hepatoma cell cultures by acting as a CysLTR1 receptor antagonist, thus unraveling a new host-virus interaction in the HCV life cycle.

Keywords

cysteinyl leukotriene receptor 1 hepatitis C virus virology

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MeSH Term

Antiviral Agents
Hepacivirus
Hepatitis C
Hepatitis C, Chronic
Humans
Propionates
Quinolines
Receptors, Leukotriene
Replicon
Virus Replication

Chemicals

Antiviral Agents
Propionates
Quinolines
Receptors, Leukotriene
verlukast
leukotriene D4 receptor
Journal Article Research Support, Non-U.S. Gov't

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