使用临床应用的药物作为胆汁酸转运蛋白NTCP的新型抑制剂降

StephenW

Sci Rep. 2017 Nov 10;7(1):15307. doi: 10.1038/s41598-017-15338-0.
Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP.Donkers JM1, Zehnder B2, van Westen GJP3, Kwakkenbos MJ4, IJzerman AP3, Oude Elferink RPJ1,5, Beuers U1,5, Urban S2,6, van de Graaf SFJ7,8.
Author information
1Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands.2Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.3Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.4Aimm Therapeutics, Amsterdam, The Netherlands.5Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands.6German Center for Infection Research, Heidelberg University, Heidelberg, Germany.7Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands. [email protected].8Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands. [email protected].

AbstractThe sodium taurocholate co-transporting polypeptide (NTCP, SLC10A1) is the main hepatic transporter of conjugated bile acids, and the entry receptor for hepatitis B virus (HBV) and hepatitis delta virus (HDV). Myrcludex B, a synthetic peptide mimicking the NTCP-binding domain of HBV, effectively blocks HBV and HDV infection. In addition, Myrcludex B inhibits NTCP-mediated bile acid uptake, suggesting that also other NTCP inhibitors could potentially be a novel treatment of HBV/HDV infection. This study aims to identify clinically-applied compounds intervening with NTCP-mediated bile acid transport and HBV/HDV infection. 1280 FDA/EMA-approved drugs were screened to identify compounds that reduce uptake of taurocholic acid and lower Myrcludex B-binding in U2OS cells stably expressing human NTCP. HBV/HDV viral entry inhibition was studied in HepaRG cells. The four most potent inhibitors of human NTCP were rosiglitazone (IC50 5.1 µM), zafirlukast (IC50 6.5 µM), TRIAC (IC50 6.9 µM), and sulfasalazine (IC50 9.6 µM). Chicago sky blue 6B (IC50 7.1 µM) inhibited both NTCP and ASBT, a distinct though related bile acid transporter. Rosiglitazone, zafirlukast, TRIAC, sulfasalazine, and chicago sky blue 6B reduced HBV/HDV infection in HepaRG cells in a dose-dependent manner. Five out of 1280 clinically approved drugs were identified that inhibit NTCP-mediated bile acid uptake and HBV/HDV infection in vitro.


PMID:29127322DOI:10.1038/s41598-017-15338-0

StephenW

Sci Rep。2017年11月10日; 7（1）：15307。 doi：10.1038 / s41598-017-15338-0。
使用临床应用的药物作为胆汁酸转运蛋白NTCP的新型抑制剂降低乙型肝炎和D病毒进入。
Donkers JM1，Zehnder B2，van Westen GJP3，Kwakkenbos MJ4，IJzerman AP3，Oude Elferink RPJ1,5，Beuers U1,5，Urban S2,6，van de Graaf SFJ7,8。
作者信息

1
    泰特加特肝脏和肠道研究所，阿姆斯特丹胃肠病学和代谢研究所，荷兰阿姆斯特丹AMC。
2
    德国海德堡海德堡大学医院感染性疾病分子病毒学系。
3
    荷兰莱顿莱顿大学莱顿医学化学药物研究学术中心。
4
    Aimm Therapeutics，阿姆斯特丹，荷兰。
五
    荷兰阿姆斯特丹阿姆斯特丹胃肠病与代谢研究所胃肠病学与肝病学系。
6
    德国海德堡海德堡大学德国感染研究中心。
7
    泰特加特肝脏和肠道研究所，阿姆斯特丹胃肠病学和代谢研究所，荷兰阿姆斯特丹AMC。 [email protected]。
8
    荷兰阿姆斯特丹阿姆斯特丹胃肠病与代谢研究所胃肠病学与肝病学系。 [email protected]。

抽象

牛磺胆酸钠共转运多肽（NTCP，SLC10A1）是结合胆汁酸的主要肝转运蛋白，是乙型肝炎病毒（HBV）和丁型肝炎病毒（HDV）的进入受体。 Myrcludex B是一种模仿HBV的NTCP结合域的合成肽，有效阻断HBV和HDV的感染。此外，Myrcludex B抑制NTCP介导的胆汁酸摄取，暗示其他NTCP抑制剂也可能是一种新的治疗HBV / HDV感染。本研究旨在确定临床应用的化合物介入NTCP介导的胆汁酸转运和HBV / HDV感染。筛选1280 FDA / EMA批准的药物以鉴定在稳定表达人NTCP的U2OS细胞中降低牛磺胆酸摄取和降低Myrcludex B结合的化合物。在HepaRG细胞中研究HBV / HDV病毒进入抑制。四种最有效的人NTCP抑制剂是罗格列酮（IC505.1μM），扎鲁司特（IC506.5μM），TRIAC（IC506.9μM）和柳氮磺胺吡啶（IC509.6μM）。芝加哥天蓝6B（IC50 7.1μM）抑制NTCP和ASBT，这是一种独特的胆汁酸转运蛋白。罗格列酮，扎鲁司特，TRIAC，柳氮磺胺吡啶和芝加哥天蓝6B以剂量依赖性方式降低HepaRG细胞中的HBV / HDV感染。鉴定出1280种临床批准的药物中有5种在体外抑制NTCP介导的胆汁酸摄取和HBV / HDV感染。

结论：
    29127322
DOI：
    10.1038 / s41598-017-15338-0

StephenW

https://www.nature.com/articles/s41598-017-15338-0