Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity.
Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity.
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DOI：
10.1016/j.jhep.2016.11.009
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发表时间：
2017-04
影响因子：
25.7
通讯作者：
Wakita T
中科院分区：
文献类型：
--
作者：
Shimura S;Watashi K;Fukano K;Peel M;Sluder A;Kawai F;Iwamoto M;Tsukuda S;Takeuchi JS;Miyake T;Sugiyama M;Ogasawara Y;Park SY;Tanaka Y;Kusuhara H;Mizokami M;Sureau C;Wakita T
牛磺胆酸钠共转运多肽（NTCP）是大多数乙型肝炎病毒（HBV）特异性进入抑制剂的主要靶点。不幸的是，这些药物也阻断了胆汁酸向肝细胞的NTCP转运，因此有可能引起不良反应。我们的目标是鉴定在维持NTCP转运蛋白功能的同时抑制HBV进入的小分子。我们利用过表达NTCP的HepG2细胞和原代人肝细胞，对一系列环孢素（CsA）衍生物的抗hbv活性和NTCP结合特异性进行了表征。对四种最有效的衍生物进行了测试，以防止HBV进入，但保持NTCP转运蛋白的功能。分析了它们对不同HBV基因型的抗病毒活性。我们发现几种CsA衍生物具有亚微摩尔IC50抑制HBV感染。其中，SCY446和SCY450对钙调神经磷酸酶（CN）和亲环蛋白（CyPs）活性较低。这表明，这些化合物直接与NTCP相互作用以抑制病毒对宿主细胞的附着，而不具有免疫抑制功能。重要的是，我们发现SCY450和SCY995不会损害ntcp依赖性胆汁酸的摄取，并抑制多种HBV基因型，包括临床相关的核苷类似物耐药HBV分离物。这是第一个小分子选择性抑制HBV进入而不降低NTCP转运蛋白活性的例子。提示抗hbv活性可从胆汁酸转运中分离出来。这些具有广泛活性的抗hbv分子是开发副作用较小的新药的潜在候选者。在这项研究中，我们发现了选择性抑制乙型肝炎病毒（HBV）进入的新化合物，并且不损害胆汁酸的摄取。我们的证据为开发副作用更小的抗hbv药物提供了一种新的策略。
The sodium taurocholate co-transporting polypeptide (NTCP) is the main target of most hepatitis B virus (HBV) specific entry inhibitors. Unfortunately, these agents also block NTCP transport of bile acids into hepatocytes, and thus have the potential to cause adverse effects. We aimed to identify small molecules that inhibit HBV entry while maintaining NTCP transporter function. We characterized a series of cyclosporine (CsA) derivatives for their anti-HBV activity and NTCP binding specificity using HepG2 cells overexpressing NTCP and primary human hepatocytes. The four most potent derivatives were tested for their capacity to prevent HBV entry, but maintain NTCP transporter function. Their antiviral activity against different HBV genotypes was analysed. We identified several CsA derivatives that inhibited HBV infection with a sub-micromolar IC50. Among them, SCY446 and SCY450 showed low activity against calcineurin (CN) and cyclophilins (CyPs), two major CsA cellular targets. This suggested that instead, these compounds interacted directly with NTCP to inhibit viral attachment to host cells, and have no immunosuppressive function. Importantly, we found that SCY450 and SCY995 did not impair the NTCP-dependent uptake of bile acids, and inhibited multiple HBV genotypes including a clinically relevant nucleoside analog-resistant HBV isolate. This is the first example of small molecule selective inhibition of HBV entry with no decrease in NTCP transporter activity. It suggests that the anti-HBV activity can be functionally separated from bile acid transport. These broadly active anti-HBV molecules are potential candidates for developing new drugs with fewer adverse effects. In this study, we identified new compounds that selectively inhibited hepatitis B virus (HBV) entry, and did not impair bile acid uptake. Our evidence offers a new strategy for developing anti-HBV drugs with fewer side effects.
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DOI：
10.1038/nrmicro3098
发表时间：
2013-10
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
7.6
作者：
Lin, Kai;Gallay, Philippe
通讯作者：
Gallay, Philippe
影响因子：
8.9
作者：
Li J;Tong S
通讯作者：
Tong S
影响因子：
7.6
作者：
Blanchet, Matthieu;Sureau, Camille;Labonte, Patrick
通讯作者：
Labonte, Patrick
影响因子：
6
作者：
Ishida, Yuji;Yamasaki, Chihiro;Tateno, Chise
通讯作者：
Tateno, Chise