Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide.
Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide.
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DOI：
10.1038/s41598-018-20987-w
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发表时间：
2018-02-09
影响因子：
4.6
通讯作者：
Watashi K
中科院分区：
文献类型：
--
作者：
Kaneko M;Futamura Y;Tsukuda S;Kondoh Y;Sekine T;Hirano H;Fukano K;Ohashi H;Saso W;Morishita R;Matsunaga S;Kawai F;Ryo A;Park SY;Suzuki R;Aizaki H;Ohtani N;Sureau C;Wakita T;Osada H;Watashi K
目前的抗乙肝病毒药物包括干扰素和核糖核酸类似物，能有效地抑制乙肝病毒感染。然而，由于很难从慢性感染的肝脏中清除乙肝病毒，迫切需要针对新分子的替代抗乙肝药物。在这项研究中，我们应用化学阵列高通量筛选与乙肝病毒进入受体牛磺胆酸钠共转运多肽(NTCP)相互作用的小分子。从大约30,000个化合物中，我们确定了74个NTCP相互作用的候选化合物，其中5个化合物被证明在细胞培养中可以抑制乙肝病毒感染。其中一种化合物NPD8716是一种香豆素衍生物，它与NTCP相互作用，在不产生细胞毒性的情况下抑制乙肝病毒感染。与其NTCP相互作用能力一致，该化合物被证明能阻断病毒对宿主肝细胞的附着。NPD8716也可以预防丁型肝炎病毒的感染，但不能预防丙型肝炎病毒的感染，这与NPD8716特异性抑制NTCP介导的感染是一致的。对化合物的分析表明，化合物的抗乙肝病毒活性与其对NTCP的亲和力和对NTCP介导的胆汁酸摄取的抑制能力有明显的相关性。这些结果首次表明，化学阵列技术代表了一个强大的平台来寻找新的病毒进入抑制剂。
Current anti-hepatitis B virus (HBV) agents including interferons and nucleos(t)ide analogs efficiently suppress HBV infection. However, as it is difficult to eliminate HBV from chronically infected liver, alternative anti-HBV agents targeting a new molecule are urgently needed. In this study, we applied a chemical array to high throughput screening of small molecules that interacted with sodium taurocholate cotransporting polypeptide (NTCP), an entry receptor for HBV. From approximately 30,000 compounds, we identified 74 candidates for NTCP interactants, and five out of these were shown to inhibit HBV infection in cell culture. One of such compound, NPD8716, a coumarin derivative, interacted with NTCP and inhibited HBV infection without causing cytotoxicity. Consistent with its NTCP interaction capacity, this compound was shown to block viral attachment to host hepatocytes. NPD8716 also prevented the infection with hepatitis D virus, but not hepatitis C virus, in agreement with NPD8716 specifically inhibiting NTCP-mediated infection. Analysis of derivative compounds showed that the anti-HBV activity of compounds was apparently correlated with the affinity to NTCP and the capacity to impair NTCP-mediated bile acid uptake. These results are the first to show that the chemical array technology represents a powerful platform to identify novel viral entry inhibitors.
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DOI：
10.2174/1568011053352622
发表时间：
2005-01-01
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
Okamoto, Toshihiro;Kobayashi, Tadashi;Yoshida, Shinichi
通讯作者：
Yoshida, Shinichi
DOI：
10.1007/978-1-60761-845-4_8
发表时间：
2010-01-01
期刊：
SMALL MOLECULE MICROARRAYS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Miyazaki, Isao;Simizu, Siro;Osada, Hiroyuki
通讯作者：
Osada, Hiroyuki
影响因子：
7.6
作者：
Blanchet, Matthieu;Sureau, Camille;Labonte, Patrick
通讯作者：
Labonte, Patrick
影响因子：
46.9
作者：
Petersen, Joerg;Dandri, Maura;Urban, Stephan
通讯作者：
Urban, Stephan
影响因子：
6
作者：
Ishida, Yuji;Yamasaki, Chihiro;Tateno, Chise
通讯作者：
Tateno, Chise