通过Sp1开发新型抗乙型肝炎病毒药物。

StephenW

Sci Rep. 2020 Jan 8;10(1):47. doi: 10.1038/s41598-019-56842-9.
Development of a novel anti-hepatitis B virus agent via Sp1.
Hayakawa M1, Umeyama H2, Iwadate M2, Taguchi YH3, Yano Y4, Honda T5, Itami-Matsumoto S1, Kozuka R1, Enomoto M1, Tamori A1, Kawada N1, Murakami Y6,7.
Author information

1
    Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.
2
    Department of Biological Sciences, Chuo University, Tokyo, 112-8551, Japan.
3
    Department of Physics, Chuo University, Tokyo, 112-8551, Japan.
4
    Division of Gastroenterology, Department of Internal of Medicine, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
5
    Division of Gastroenterology, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
6
    Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan. [email protected].
7
    Department of Molecular Pathology, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-Ku, Tokyo, 160-8402, Japan. [email protected].

Abstract

Nucleos(t)ide analog (NA) therapy has proven effective in treating chronic hepatitis B. However, NAs frequently result in viral relapse after the cessation of therapy. This is because NAs cannot fully eliminate the viral episomal covalently closed circular DNA (cccDNA) in the nucleus. In this study, we identified small molecular compounds that control host factors related to viral replication using in silico screening with simulated annealing based on bioinformatics for protein-ligand flexible docking. Twelve chemical compound candidates for alpha-glucosidase (AG) inhibitors were identified from a library of chemical compounds and used to treat fresh human hepatocytes infected with HBV. They were then monitored for their anti-viral effects. HBV replication was inhibited by one candidate (1-[3-(4-tert-butylcyclohexyl)oxy-2-hydroxypropyl]-2,2,6,6-tetramethylpiperidin-4-ol) in a dose-dependent manner. This compound significantly reduced ccc DNA production, compared to Entecavir (p < 0.05), and had a lower anti-AG effect. Gene expression analysis and structural analysis of this compound showed that its inhibitive effect on HBV was via interaction with Sp1. The nuclear transcription factor Sp1 acts on multiple regions of HBV to suppress HBV replication. Identifying candidates that control nuclear transcription factors facilitate the development of novel therapies. Drugs with a mechanism different from NA are promising for the elimination of HBV.

PMID:
    31913341
DOI:
    10.1038/s41598-019-56842-9

StephenW

Sci Rep.2020年1月8日； 10（1）：47。 doi：10.1038 / s41598-019-56842-9。
通过Sp1开发新型抗乙型肝炎病毒药物。
早川M1，梅山H2，岩手M2，田口YH3，矢野Y4，本田T5，伊丹松本S1，小冢R1，江之本M1，田森A1，川田N1，村上Y6,7。
作者信息

1个
    大阪市立大学医学研究科肝病科，大阪545-8585，日本。
2
    中央大学生物科学系，东京，112-8551，日本。
3
    中央大学物理系，东京，112-8551，日本。
4
    日本神户大学医学研究生院内科学系消化内科，650-0017，日本。
5
    名古屋大学大学院医学系内科消化内科，日本名古屋466-8550。
6
    大阪市立大学医学研究科肝病科，大阪545-8585，日本。 [email protected]。
7
    东京医科大学分子病理学系，日本东京新宿区新宿6-1-1，160-8402。 [email protected]。

抽象

核苷类似物（NA）治疗已被证明可有效治疗慢性乙型肝炎。但是，NAs常常在停止治疗后导致病毒复发。这是因为NA不能完全消除细胞核中的病毒游离共价封闭的环状DNA（cccDNA）。在这项研究中，我们确定了小分子化合物，这些化合物可通过计算机模拟筛选和基于蛋白质信息配体灵活对接的生物信息学的模拟退火技术，来控制与病毒复制相关的宿主因子。从化合物库中鉴定出十二种用于α-葡萄糖苷酶（AG）抑制剂的候选化合物，并用于治疗感染了HBV的新鲜人肝细胞。然后监测它们的抗病毒作用。 HBV复制被一种候选药物（1- [3-（4-叔丁基环己基）氧基-2-羟丙基] -2,2,6,6-四甲基哌啶-4-醇）抑制，且呈剂量依赖性。与恩替卡韦相比，该化合物显着降低了ccc DNA的产生（p << 0.05），并且抗AG效应较低。该化合物的基因表达分析和结构分析表明，该化合物对HBV的抑制作用是通过与Sp1相互作用而实现的。核转录因子Sp1作用于HBV的多个区域以抑制HBV复制。识别控制核转录因子的候选物有助于新疗法的发展。具有不同于NA机制的药物有望消除HBV。

PMID：
    31913341
DOI：
    10.1038 / s41598-019-56842-9

StephenW

https://www.nature.com/articles/s41598-019-56842-9.pdf