通过N-羟基异喹啉酮和相关的聚氧化杂环抑制乙型肝炎病毒复

StephenW

Antiviral Res. 2017 Apr 24. pii: S0166-3542(17)30005-0. doi: 10.1016/j.antiviral.2017.04.012. [Epub ahead of print]
Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocycles.
Edwards TC1, Lomonosova E2, Patel JA3, Li Q4, Villa JA5, Gupta AK6, Morrison LA7, Bailly F8, Cotelle P9, Giannakopoulou E10, Zoidis G11, Tavis JE12.
1   Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].
2    Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].
3    Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].
4    Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].
5    Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].
6    Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].
7    Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].
8    University of Lille, INSERM, UMR-S 1172, Jean-Pierre Aubert Research Center, Lille, France. Electronic address: [email protected].
9    University of Lille, INSERM, UMR-S 1172, Jean-Pierre Aubert Research Center, Lille, France. Electronic address: [email protected].
10    School of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: [email protected].
11    School of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: [email protected].
12    Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].
Abstract

We previously reported low sensitivity of the hepatitis B virus (HBV) ribonuclease H (RNaseH) enzyme to inhibition by N-hydroxyisoquinolinedione (HID) compounds. Subsequently, our biochemical RNaseH assay was found to have a high false negative rate for predicting HBV replication inhibition, leading to underestimation of the number of HIDs that inhibit HBV replication. Here, 39 HID compounds and structurally related polyoxygenated heterocycles (POH), N-hydroxypyridinediones (HPD), and flutimides were screened for inhibition of HBV replication in vitro. Inhibiting the HBV RNaseH preferentially blocks synthesis of the positive-polarity DNA strand and causes accumulation of RNANA heteroduplexes. Eleven HIDs and one HPD preferentially inhibited HBV positive-polarity DNA strand accumulation. EC50s ranged from 0.69 μM to 19 μM with therapeutic indices from 2.4 to 71. Neither the HIDs nor the HPD had an effect on the ability of the polymerase to elongate DNA strands in capsids. HBV RNaseH inhibition by the HIDs was confirmed with an improved RNaseH assay and by detecting accumulation RNANA heteroduplexes in HBV capsids from cells treated with a representative HID. Therefore, the HID scaffold is more promising for anti-HBV drug discovery than we originally reported, and the HPD scaffold may hold potential for antiviral development. The preliminary structure-activity relationship will guide optimization of the HID/HPDs as HBV inhibitors.

Copyright © 2017. Published by Elsevier B.V.
KEYWORDS:

Flutimide; Hepatitis B virus; N-hydroxyisoquinolinediones; N-hydroxypyridinediones; Polyoxygenated heterocycles; Ribonuclease H

PMID:
    28450058
DOI:
    10.1016/j.antiviral.2017.04.012

StephenW

抗病毒研究2017年4月24日。pii：S0166-3542（17）30005-0。 doi：10.1016 / j.antiviral.2017.04.012。 [提前印刷]
通过N-羟基异喹啉酮和相关的聚氧化杂环抑制乙型肝炎病毒复制。
Edwards TC1，Lomonosova E2，Patel JA3，Li Q4，Villa JA5，Gupta AK6，Morrison LA7，Bailly F8，Cotelle P9，Giannakopoulou E10，Zoidis G11，Tavis JE12。
1 Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center，Saint Louis University School of Medicine，St.Louis，MO，USA。电子地址：[email protected]。
2 Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center，Saint Louis University School of Medicine，St.Louis，MO，USA。电子地址：[email protected]。
3 Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center，Saint Louis University School of Medicine，St.Louis，MO，USA。电子地址：[email protected]。
4 Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center，Saint Louis University School of Medicine，St.Louis，MO，USA。电子地址：[email protected]。
5 Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center，Saint Louis University School of Medicine，St.Louis，MO，USA。电子邮件地址：[email protected]。
6 Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center，Saint Louis University School of Medicine，St.Louis，MO，USA。电子地址：[email protected]。
7 Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center，Saint Louis University School of Medicine，St.Louis，MO，USA。电子地址：[email protected]。
8里奇大学INSERM，UMR-S 1172，法国里尔Jean-Pierre Aubert研究中心。电子地址：[email protected]。
9里尔大学，INSERM，UMR-S 1172，Jean-Pierre Aubert研究中心，法国里尔。电子地址：[email protected]。
雅典希腊雅典国家和卡波第斯特大学药学化学系药学院10医学院。电子地址：[email protected]。
雅典雅典雅典国家医学化学系药物化学系卫生科学学院雅典雅典希腊Kapodistrian大学药学院药学院。电子地址：[email protected]。
12 Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center，Saint Louis University School of Medicine，St.Louis，MO，USA。电子地址：[email protected]。
抽象

我们之前报道了乙型肝炎病毒（HBV）核糖核酸酶H（RNaseH）酶对N-羟基异喹啉二酮（HID）化合物的抑制的低敏感性。随后，我们的生化RNaseH测定被发现具有高的假阴性率用于预测HBV复制抑制，导致低估抑制HBV复制的HID的数量。在此，筛选39个HID化合物和结构相关的聚氧化杂环（POH），N-羟基吡啶二酮（HPD）和氟替丁，以体外抑制HBV复制。抑制HBV RNA酶H优先阻断正极性DNA链的合成并引起RNA的积累：DNA异源双链体。 11个HID和1个HPD优先抑制HBV阳性极性DNA链积累。 EC50s范围从0.69μM到19μM，治疗指数从2.4到71. HID和HPD都不影响聚合酶在衣壳中伸长DNA链的能力。通过改进的RNaseH测定和通过检测来自用HID处理的细胞的HBV衣壳中的累积RNA：DNA异源双链体来证实HIDs的HBV RNA酶H抑制。因此，HID支架比我们最初报道的抗HBV药物发现更有希望，HPD支架可能具有抗病毒发展的潜力。初步结构 - 活性关系将指导HID / HPD作为HBV抑制剂的优化。

版权所有©2017. Elsevier B.V.发行。
关键词：

氟代酰胺;乙型肝炎病毒N-羟基异喹啉酮; N-羟基吡啶二酮;多氧杂环;核糖核酸酶H

PMID：
    28450058
DOI：
    10.1016 / j.antiviral.2017.04.012