期刊
LIVER INTERNATIONAL
卷 41, 期 6, 页码 1344-1357出版社
WILEY
DOI: 10.1111/liv.14839
关键词
ABC transporters; bile secretion; cell models; cholestatic liver diseases; molecular docking; targeted pharmacotherapy
资金
- Ministere de l'Enseignement Superieur, de la Recherche et de l'Innovation
- Agence Nationale de la Recherche [ANR-15-CE14-0008-01, ANR-19-CE17-0020-01 IMOTEP]
- French Association for the Study of the Liver (AFEF)
- Region Nouvelle Aquitaine
- Institut National de la Sante et de la Recherche Medicale (AAP NA 2019 VICTOR)
- Agence Nationale de la Recherche (ANR) [ANR-15-CE14-0008] Funding Source: Agence Nationale de la Recherche (ANR)
Certain CFTR correctors can rescue the maturation and canalicular localization of ABCB4 variants, but do not restore their secretion activity and also inhibit the activity of wild type ABCB4. In silico molecular docking analyses suggest direct interaction of these correctors with the transporter's transmembrane domains and ATP-binding sites.
Background & aim: ABCB4 is expressed at the canalicular membrane of hepatocytes. This ATP-binding cassette (ABC) transporter is responsible for the secretion of phosphatidylcholine into bile canaliculi. Missense genetic variations of ABCB4 are correlated with several rare cholestatic liver diseases, the most severe being progressive familial intrahepatic cholestasis type 3 (PFIC3). In a repurposing strategy to correct intracellularly retained ABCB4 variants, we tested 16 compounds previously validated as cystic fibrosis transmembrane conductance regulator (CFTR) correctors. Methods: The maturation, intracellular localization and activity of intracellularly retained ABCB4 variants were analyzed in cell models after treatment with CFTR correctors. In addition, in silico molecular docking calculations were performed to test the potential interaction of CFTR correctors with ABCB4. Results: We observed that the correctors C10, C13, and C17, as well as the combinations of C3 + C18 and C4 + C18, allowed the rescue of maturation and canalicular localization of four distinct traffic-defective ABCB4 variants. However, such treatments did not permit a rescue of the phosphatidylcholine secretion activity of these defective variants and were also inhibitory of the activity of wild type ABCB4. In silico molecular docking analyses suggest that these CFTR correctors might directly interact with transmembrane domains and/or ATP-binding sites of the transporter. Conclusion: Our results illustrate the uncoupling between the traffic and the activity of ABCB4 because the same molecules can rescue the traffic of defective variants while they inhibit the secretion activity of the transporter. We expect that this study will help to design new pharmacological tools with potential clinical interest.
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