一种新型的三环聚酮，vanitaracin A，特异性抑制B型肝炎和D病

StephenW

J Virol. 2015 Sep 16. pii: JVI.01855-15. [Epub ahead of print]
A novel tricyclic polyketide, vanitaracin A, specifically inhibits the entry of hepatitis B and D viruses through targeting NTCP.Kaneko M1, Watashi K2, Kamisuki S3, Matsunaga H3, Iwamoto M1, Kawai F4, Ohashi H1, Tsukuda S5, Shimura S6, Suzuki R7, Aizaki H7, Sugiyama M8, Park SY4, Ito T9, Ohtani N3, Sugawara F3, Tanaka Y10, Mizokami M8, Sureau C11, Wakita T7.
Author information

• 1Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.
• 2Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan Department of Applied Biological Science, Tokyo University of Science, Noda, Japan [email protected].
• 3Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.
• 4Protein Design Laboratory, Yokohama City University, Yokohama, Japan.
• 5Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan Micro-signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Wako, Japan.
• 6Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan SCYNEXIS, Inc., Durham, NC, USA.
• 7Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
• 8The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
• 9Digestive Diseases Center, Showa University Koto-Toyosu Hospital, Tokyo, Japan.
• 10Department of Virology and Liver Unit, Nagoya City University Graduate School of Medicinal Sciences, Nagoya, Japan.
• 11Laboratoire de Virologie Moléculaire, Institut National de la Transfusion Sanguine (INTS), Paris, France.
  

AbstractAnti-hepatitis B virus (HBV) drugs are currently limited to nucleos(t)ide analogs (NAs) and interferons. For a challenge of drug development, it is demanded to identify small molecules that suppress HBV infection from new chemical sources. Here, from a fungal-derived secondary metabolite library, we identify a structurally novel tricyclic polyketide, named vanitaracin A, which specifically inhibits HBV infection. Vanitaracin A inhibited the viral entry process with a submicromolar IC50 (IC50 = 0.61 ± 0.23 μM) without evident cytotoxicity (CC50 > 256 μM, selectivity index > 419) in primary human hepatocytes. Vanitaracin A did not affect HBV replication process. This compound was found to directly interact with the HBV entry receptor, sodium taurocholate cotransporting polypeptide (NTCP), and impaired its bile acid transport activity. Consistent with this NTCP targeting, antiviral activity of vanitaracin A was observed with hepatitis D virus (HDV), but not hepatitis C virus. Importantly, vanitaracin A inhibited infection of all the HBV genotypes tested (genotype A-D) and clinically-relevant NA-resistant HBV isolates. Thus, we identified a fungal metabolite, vanitaracin A, which was a potent, well-tolerated, and broadly active inhibitor of HBV and HDV entry. This compound, or its related analogs, could be part of an antiviral strategy for preventing reinfection with HBV, including clinically-relevant nucleos(t)ide analog-resistant virus.
IMPORTANCE: For achieving better treatment and prevention against hepatitis B virus (HBV), anti-HBV agents targeting a new molecule have been greatly demanded. Although sodium taurocholate cotransporting polypeptide (NTCP) has recently been reported as an essential host factor for HBV entry, there is limited number of report that identify new compounds targeting NTCP and inhibiting HBV entry. Here, from an uncharacterized chemical library, we isolated a structurally new compound, named vanitaracin A, which inhibited the entry process of HBV and hepatitis D virus (HDV). This compound was suggested to directly interact with NTCP and inhibit its transporter activity. Importantly, vanitaracin A inhibited the entry of all the HBV genotypes examined and that of a clinically-relevant nucleos(t)ide analog-resistant HBV isolate.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.

StephenW

病毒学杂志。 2015年九月16 PII：JVI.01855-15。 [打印EPUB提前]
一种新型的三环聚酮，vanitaracin A，特异性抑制B型肝炎和D病毒通过针对NTCP的条目。
金子M1，渡K2，Kamisuki S3，松永H3，岩本M1，河合F4，大桥H1，佃S5，志村S6，铃木R7，Aizaki H7，杉山M8，公园SY4，伊藤T9，大谷N3，菅原F3，田中Y10 ，Mizokami M8，Sureau C11，胁田T7。
作者信息

    教研室病毒学二，传染病东京理科大学研究所，东京，应用生物科学系日本，野田佳彦，日本。
    教研室病毒学二，传染病东京理科大学研究所，东京，应用生物科学系日本，野田佳彦，日本[email protected]的。
    3Department应用生物科学，东京理科大学，野田佳彦，日本。
    4Protein设计实验室，横滨市立大学，日本横滨。
    5Department病毒学二，国家传染病研究所，日本东京，日本微型信号调节技术部，理研中心生命科学技术，光，日本。
    6Department病毒学二，国家传染病研究所，日本东京SCYNEXIS公司，北卡罗来纳州达勒姆，美国。
    7Department病毒学二，国家传染病研究所，日本东京。
    第八研究中心肝炎免疫学，国家中心的全球健康和医学，市川，日本。
    9Digestive疾病中心，昭和大学江东丰洲医院，日本东京。
    10Department病毒学和肝单位，药用科学名古屋市立大学研究生院，日本名古屋。
    11Laboratoire德VirologieMoléculaire，研究所国家德拉输血血红色（INTS），法国巴黎。

抽象的

抗乙肝病毒（HBV）的药物目前只限于核苷（酸）类似物（NAS）和干扰素。对于药物开发的一个挑战，它要求以确定小分子抑制来自新的化学来源HBV感染。在这里，从真菌衍生的次生代谢产物库，我们确定了结构新颖的三环聚酮，命名vanitaracin A，其特异性抑制H​​BV感染。 Vanitaracin一个抑制了亚微IC50（IC50 = 0.61±0.23μM）无明显毒性的病毒进入过程（CC50> 256微米，选择性指数> 419）在原代人肝细胞。 Vanitaracin A未影响HBV的复制过程。此化合物被发现直接与HBV的条目受体，牛磺胆酸钠cotransporting多肽（NTCP）相互作用，并削弱其胆汁酸转运活性。与此相一致NTCP定位，vanitaracin A的抗病毒活性，观察到丁型肝炎病毒（HDV），但不是C型肝炎病毒。重要的是，vanitaracin所有HBV基因型的抑制感染测试（基因型AD）和临床相关的NA-HBV耐药株。因此，我们确定了真菌代谢物，vanitaracin A，其是HBV和HDV条目的强效，耐受性良好，并具有广泛的活性抑制剂。该化合物，或它的相关的类似物，可以是抗病毒策略，用于防止再感染HBV的，包括临床相关核苷（酸）的ide类似物抗性病毒的一部分。
重要性：

对于抗乙型肝炎病毒（HBV），针对新分子的抗HBV药物达到更好的治疗和预防都有了很大的要求。虽然牛磺胆酸钠cotransporting多肽（NTCP），最近有报道作为用于HBV的条目的必要宿主因子，有报告的数目有限标识靶向NTCP和抑制HBV的条目的新化合物。在这里，从一个未鉴定的化学库，我们分离出了一种新结构化合物，命名为vanitaracin A，其抑制乙肝病毒和丁型肝炎病毒（HDV）的输入过程。此化合物有人建议直接与NTCP相互作用并抑制其转运蛋白活性。重要的是，vanitaracin一个禁止所有检查的HBV基因型的进入临床相关的核苷（酸）类似物IDE抗乙肝病毒分离物和。

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