N-羟基异喹啉二酮和N-羟基吡啶二酮核糖核酸酶H抑制剂对HBV复

StephenW

Antiviral Res. 2019 Feb 12. pii: S0166-3542(18)30640-5. doi: 10.1016/j.antiviral.2019.02.005. [Epub ahead of print]
Inhibition of HBV replication by N-hydroxyisoquinolinedione and N-hydroxypyridinedione ribonuclease H inhibitors.
Edwards TC1, Mani N2, Dorsey B3, Kakarla R4, Rijnbrand R5, Sofia MJ6, Tavis JE7.
Author information

1
    Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA; Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].
2
    Arbutus Biopharma Incorporated, Warminster, PA, USA. Electronic address: [email protected].
3
    Arbutus Biopharma Incorporated, Warminster, PA, USA. Electronic address: [email protected].
4
    Arbutus Biopharma Incorporated, Warminster, PA, USA. Electronic address: [email protected].
5
    Arbutus Biopharma Incorporated, Warminster, PA, USA. Electronic address: [email protected].
6
    Arbutus Biopharma Incorporated, Warminster, PA, USA. Electronic address: [email protected].
7
    Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA; Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].

Abstract

We recently developed a screening system capable of identifying and evaluating inhibitors of the Hepatitis B virus (HBV) ribonuclease H (RNaseH), which is the only HBV enzyme not targeted by current anti-HBV therapies. Inhibiting the HBV RNaseH blocks synthesis of the positive-polarity DNA strand, causing early termination of negative-polarity DNA synthesis and accumulation of RNANA heteroduplexes. We previously reported inhibition of HBV replication by N-hydroxyisoquinolinediones (HID) and N-hydroxypyridinediones (HPD) in human hepatoma cells. Here, we report results from our ongoing efforts to develop more potent anti-HBV RNaseH inhibitors in the HID/HPD compound classes. We synthesized and screened additional HIDs and HPDs for preferential suppression of positive-polarity DNA in cells replicating HBV. Three of seven new HIDs inhibited HBV replication, however, the therapeutic indexes (TI = CC50/EC50) did not improve over what we previously reported. All nine of the HPDs inhibited HBV replication with EC50s ranging from 110 nM to 4 μM. Cellular cytotoxicity was evaluated by four assays and CC50s ranged from 15 to >100 μM. The best compounds have a calculated TI of >300, which is a 16-fold improvement over the primary HPD hit. These studies indicate that the HPD compound class holds potential for antiviral discovery.

Copyright © 2019. Published by Elsevier B.V.
KEYWORDS:

Antiviral; HBV; N-hydroxyisoquinolinediones; N-hydroxypyridinediones; Ribonuclease H; Structure-activity relationship

PMID:
    30768944
DOI:
    10.1016/j.antiviral.2019.02.005

StephenW

抗病毒药物2019年2月12日.pii：S0166-3542（18）30640-5。 doi：10.1016 / j.antiviral.2019.02.005。 [印刷前的电子版]
N-羟基异喹啉二酮和N-羟基吡啶二酮核糖核酸酶H抑制剂对HBV复制的抑制作用。
Edwards TC1，Mani N2，Dorsey B3，Kakarla R4，Rijnbrand R5，Sofia MJ6，Tavis JE7。
作者信息

1
    美国密苏里州圣路易斯市圣路易斯大学医学院分子微生物学和免疫学系;圣路易斯大学肝脏中心，圣路易斯大学医学院，圣路易斯，密苏里州，美国。电子地址：[email protected]。
2
    Arbutus Biopharma Incorporated，Warminster，PA，USA。电子地址：[email protected]。
3
    Arbutus Biopharma Incorporated，Warminster，PA，USA。电子地址：[email protected]。
4
    Arbutus Biopharma Incorporated，Warminster，PA，USA。电子地址：[email protected]。
五
    Arbutus Biopharma Incorporated，Warminster，PA，USA。电子地址：[email protected]。
6
    Arbutus Biopharma Incorporated，Warminster，PA，USA。电子地址：[email protected]。
7
    美国密苏里州圣路易斯市圣路易斯大学医学院分子微生物学和免疫学系;圣路易斯大学肝脏中心，圣路易斯大学医学院，圣路易斯，密苏里州，美国。电子地址：[email protected]。

抽象

我们最近开发了一种能够鉴定和评估乙型肝炎病毒（HBV）核糖核酸酶H（RNaseH）抑制剂的筛选系统，这是目前抗HBV治疗不能靶向的唯一HBV酶。抑制HBV RNaseH阻断正极性DNA链的合成，导致负极性DNA合成的早期终止和RNA：DNA异源双链的积累。我们先前报道了人肝癌细胞中N-羟基异喹啉二酮（HID）和N-羟基吡啶二酮（HPD）对HBV复制的抑制作用。在这里，我们报告了我们正在努力在HID / HPD化合物类别中开发更有效的抗HBV RNaseH抑制剂的结果。我们合成并筛选了额外的HID和HPD，以优先抑制复制HBV的细胞中的正极性DNA。七种新HID中的三种抑制HBV复制，然而，治疗指数（TI = CC50 / EC50）并未改善我们之前报道的情况。所有9种HPD均抑制HBV复制，EC50范围为110nM至4μM。通过四种测定评估细胞的细胞毒性，CC50的范围为15至>100μM。最佳化合物的计算TI> 300，比主要HPD命中率提高了16倍。这些研究表明，HPD化合物类具有抗病毒发现的潜力。

版权所有©2019。Elsevier B.V.
关键词：

抗病毒; HBV;的N- hydroxyisoquinolinediones;的N- hydroxypyridinediones;核糖核酸酶H;结构 - 活动关系

结论：
    30768944
DOI：
    10.1016 / j.antiviral.2019.02.005