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 (EC50 ± standard deviation) of 9 ± 0.3 μM and a maximum HCV RNA level reduction of approximatively 1 log10 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.
Highlights
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
ATP-binding cassette (ABC) transporter (e.g., MRP-1) efflux on the antiviral activity of the hepatitis C virus (HCV) protease inhibitor telaprevir, we measured HCV RNA levels in Huh7.5 cells stably harboring a genotype 1b HCV-subgenomic replicon (SGR) treated with 1 M of telaprevir in combination with 50 M of MK-571
In Huh7.5 cells stably harboring a genotype 1b HCV-SGR, 48 h of treatment with MK-571 induced a dose-dependent decrease of HCV-SGR RNA, with an 50% effective concentration (EC50) of 9.0 Ϯ 0.3 M (Fig. 2A) and a maximal HCV-SGR RNA reduction of approximatively 11-fold at 50 M (Fig. 2B)
Summary
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. In patients who fail to achieve a cure of the infection, HCV variants carrying resistance-associated substitutions (RASs) on their genome, i.e., substitutions that confer reduced susceptibility to the administered drugs, are generally selected [6]. Their long-term persistence after treatment raises issues as to subsequent retreatment. The high cost of last-generation DAA regimens limits access to care in low-income areas, while the management of special patient groups, such as those with advanced liver disease or renal failure, may be problematic with current drugs
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