Ruiz Isaac, Nevers Quentin, Hernández Eva, Ahnou Nazim, Brillet Rozenn, Softic Laurent, Donati Flora, Berry Francois, Hamadat Sabah, Fourati Slim, Pawlotsky Jean-Michel, Ahmed-Belkacem Abdelhakim
Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Team "Viruses, Hepatology, Cancers", Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
Department of Hepatology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
Antimicrob Agents Chemother. 2020 May 21;64(6). doi: 10.1128/AAC.02078-19.
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.
喹啉类化合物MK - 571是最常用的多药耐药蛋白1（MRP - 1）抑制剂，但它最初是作为半胱氨酰白三烯受体1（CysLTR1）拮抗剂开发的。在研究MRP - 1对抗丙型肝炎病毒（HCV）直接作用抗病毒药物（DAA）疗效的调节作用时，我们意外发现化合物MK - 571单独使用时具有抗HCV作用。这种抗HCV活性在稳定携带亚基因组1b型复制子的Huh7.5细胞中得到了表征。给予MK - 571后，观察到HCV RNA水平呈剂量依赖性下降，50%有效浓度（EC±标准差）为9±0.3μM，HCV RNA水平最大降低约1 log。MK - 571还以剂量依赖性方式降低了HCV全长J6/JFH1模型的复制。然而，MRP - 1的两种特异性抑制剂丙磺舒和芹菜素同二聚体（APN）对HCV复制没有影响。相反，CysLTR1拮抗剂SR2640以剂量依赖性方式增加HCV亚基因组复制子（SGR）RNA水平，最大增加10倍。此外，天然CysLTR1激动剂（LTD4）或拮抗剂（扎鲁司特、西那司特和SR2640）与MK - 571联合使用完全逆转了其抗病毒作用，表明其抗HCV活性与CysLTR1有关，而不是与MRP - 1抑制有关。总之，我们表明MK - 571通过作为CysLTR1受体拮抗剂抑制肝癌细胞培养中的HCV复制，从而揭示了HCV生命周期中一种新的宿主 - 病毒相互作用。
