曲格列酮阻止牛磺胆酸钠协同转运多肽和乙型肝炎病毒进入

StephenW

Front Microbiol. 2019 Jan 8;9:3257. doi: 10.3389/fmicb.2018.03257. eCollection 2018.
Troglitazone Impedes the Oligomerization of Sodium Taurocholate Cotransporting Polypeptide and Entry of Hepatitis B Virus Into Hepatocytes.
Fukano K1,2, Tsukuda S1,3, Oshima M1,4, Suzuki R1, Aizaki H1, Ohki M5, Park SY5, Muramatsu M1, Wakita T1, Sureau C6, Ogasawara Y2, Watashi K1,4,7.
Author information

1
    Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
2
    Department of Analytical Biochemistry, Meiji Pharmaceutical University, Kiyose, Japan.
3
    Liver Cancer Prevention Research Unit, Center for Integrative Medical Sciences, RIKEN, Wako, Japan.
4
    Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.
5
    Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
6
    Laboratoire de Virologie Moléculaire, Institut National de la Transfusion Sanguine, CNRS, INSERM U1134, Paris, France.
7
    JST CREST, Saitama, Japan.

Abstract

Current anti-hepatitis B virus (HBV) agents, which include nucleos(t)ide analogs and interferons, can significantly suppress HBV infection. However, there are limitations in the therapeutic efficacy of these agents, indicating the need to develop anti-HBV agents with different modes of action. In this study, through a functional cell-based chemical screening, we found that a thiazolidinedione, troglitazone, inhibits HBV infection independently of the compound's ligand activity for peroxisome proliferator-activated receptor γ (PPARγ). Analog analysis suggested chemical moiety required for the anti-HBV activity and identified ciglitazone as an analog having higher anti-HBV potency. Whereas, most of the reported HBV entry inhibitors target viral attachment to the cell surface, troglitazone blocked a process subsequent to viral attachment, i.e., internalization of HBV preS1 and its receptor, sodium taurocholate cotransporting polypeptide (NTCP). We also found that NTCP was markedly oligomerized in the presence of HBV preS1, but such NTCP oligomerization was abrogated by treatment with troglitazone, but not with pioglitazone, correlating with inhibition activity to viral internalization. Also, competitive peptides that blocked NTCP oligomerization impeded viral internalization and infection. This work represents the first report identifying small molecules and peptides that specifically inhibit the internalization of HBV. This study is also significant in proposing a possible role for NTCP oligomerization in viral entry, which will shed a light on a new aspect of the cellular mechanisms regulating HBV infection.
KEYWORDS:

HBV; NTCP; entry; internalization; multimerization; oligomerization; preS1; troglitazone

PMID:
    30671048
PMCID:
    PMC6331526
DOI:
    10.3389/fmicb.2018.03257

StephenW

前微生物。 2019年1月8日; 9：3257。 doi：10.3389 / fmicb.2018.03257。 eCollection 2018。
曲格列酮阻止牛磺胆酸钠协同转运多肽和乙型肝炎病毒进入肝细胞的寡聚化。
Fukano K1,2，Tsukuda S1,3，Oshima M1,4，Suzuki R1，Aizaki H1，Ohki M5，Park SY5，Muramatsu M1，Wakita T1，Sureau C6，Ogasawara Y2，Watashi K1,4,7。
作者信息

1
    日本东京国立传染病研究所病毒学系II。
2
    明治药业大学分析生物化学系，日本清濑。
3
    日本和光日本RIKEN综合医学中心肝癌预防研究室。
4
    日本野田大学东京理科大学应用生物科学系。
五
    横滨市立大学医学生命科学研究科药物设计实验室，日本横滨。
6
    Laboratoire deVirologieMoléculaire，Institut National de la Transfusion Sanguine，CNRS，INSERM U1134，Paris，France。
7
    JST CREST，埼玉县，日本。

抽象

目前的抗乙型肝炎病毒（HBV）药物，包括核苷（酸）类似物和干扰素，可以显着抑制HBV感染。然而，这些药剂的治疗功效存在局限性，表明需要开发具有不同作用模式的抗HBV药剂。在这项研究中，通过基于功能细胞的化学筛选，我们发现噻唑烷二酮，曲格列酮抑制HBV感染，而不依赖于化合物对过氧化物酶体增殖物激活受体γ（PPARγ）的配体活性。模拟分析表明抗HBV活性所需的化学部分，并鉴定出作为具有较高抗HBV效力的类似物的环格列酮。然而，大多数报道的HBV进入抑制剂靶向病毒附着于细胞表面，曲格列酮阻断了病毒附着后的过程，即HBV preS1及其受体，牛磺胆酸钠协同转运多肽（NTCP）的内化。我们还发现NTCP在HBV preS1存在下显着低聚，但是这种NTCP寡聚化通过用曲格列酮处理而消除，但不与吡格列酮一起消除，与对病毒内化的抑制活性相关。此外，阻断NTCP寡聚化的竞争性肽阻碍了病毒内化和感染。这项工作代表了第一份确定特异性抑制HBV内化的小分子和肽的报道。该研究对于提出NTCP寡聚化在病毒进入中的可能作用也具有重要意义，这将揭示调节HBV感染的细胞机制的新方面。
关键词：

HBV; NTCP;条目;内;多聚化;齐聚;前S1;曲格列酮

结论：
    30671048
PMCID：
    PMC6331526
DOI：
    10.3389 / fmicb.2018.03257

StephenW

https://www.frontiersin.org/arti ... icb.2018.03257/full