乙型肝炎病毒核糖核酸酶H的新型α-羟托洛芬抑制剂的细胞培

StephenW

Antiviral Res. 2017 Jun 17. pii: S0166-3542(17)30334-0. doi: 10.1016/j.antiviral.2017.06.014. [Epub ahead of print]
Efficacy and cytotoxicity in cell culture of novel α-hydroxytropolone inhibitors of Hepatitis B virus ribonuclease H.
Lomonosova E1, Daw J2, Garimallaprabhakaran AK3, Agyemang NB3, Ashani Y3, Murelli RP4, Tavis JE5.
Author information

1
    Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA; Saint Louis University Liver Center, Saint Louis, MO, USA.
2
    Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
3
    Department of Chemistry, Brooklyn College, City University of New York, Brooklyn, NY, USA.
4
    Department of Chemistry, Brooklyn College, City University of New York, Brooklyn, NY, USA; PhD Program in Chemistry, The Graduate Center of the City University of New York, New York, NY, USA.
5
    Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA; Saint Louis University Liver Center, Saint Louis, MO, USA. Electronic address: [email protected].

Abstract

Chronic Hepatitis B virus (HBV) infection is a major worldwide public health problem. Current direct-acting anti-HBV drugs target the HBV DNA polymerase activity, but the equally essential viral ribonuclease H (RNaseH) activity is unexploited as a drug target. Previously, we reported that α-hydroxytropolone compounds can inhibit the HBV RNaseH and block viral replication. Subsequently, we found that our biochemical RNaseH assay underreports efficacy of the α-hydroxytropolones against HBV replication. Therefore, we conducted a structure-activity analysis of 59 troponoids against HBV replication in cell culture. These studies revealed that antiviral efficacy is diminished by larger substitutions on the tropolone ring, identified key components in the substitutions needed for high efficacy, and revealed that cytotoxicity correlates with increased lipophilicity of the α-hydroxytropolones. These data provide key guidance for further optimization of the α-hydroxytropolone scaffold as novel HBV RNaseH inhibitors.

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

Antiviral; HBV; QSAR; RNaseH; Tropolones

PMID:
    28633989
DOI:
    10.1016/j.antiviral.2017.06.014

StephenW

抗病毒研究2017年6月17日。pii：S0166-3542（17）30334-0。 doi：10.1016 / j.antiviral.2017.06.014。 [提前印刷]
乙型肝炎病毒核糖核酸酶H的新型α-羟托洛芬抑制剂的细胞培养中的功效和细胞毒性
Lomonosova E1，Daw J2，Garimallaprabhakaran AK3，Agyemang NB3，Ashani Y3，Murelli RP4，Tavis JE5。
作者信息

1
    Department of Molecular Microbiology and Immunology，Saint Louis University School of Medicine，Saint Louis，MO，USA; Saint Louis University Liver Center，Saint Louis，MO，USA。
2
    Department of Molecular Microbiology and Immunology，Saint Louis University School of Medicine，Saint Louis，MO，USA。
3
    美国纽约布鲁克林市纽约市立大学布鲁克林学院化学系。
4
    美国纽约布鲁克林市纽约市立大学布鲁克林学院化学系;美国纽约纽约市立大学研究生院化学博士课程。
五
    Department of Molecular Microbiology and Immunology，Saint Louis University School of Medicine，Saint Louis，MO，USA; Saint Louis University Liver Center，Saint Louis，MO，USA。电子地址：[email protected]。

抽象

慢性乙型肝炎病毒（HBV）感染是全球重大的公共卫生问题。目前直接作用的抗HBV药物靶向HBV DNA聚合酶活性，但同样重要的病毒核糖核酸酶H（RNaseH）活性未被用作药物靶点。以前，我们报道α-羟托吡酮化合物可以抑制HBV核糖核酸酶H并阻断病毒复制。随后，我们发现我们的生物化学RNaseH测定报道了α-羟托吡酮对HBV复制的疗效。因此，我们在细胞培养中进行了59种质粒对HBV复制的结构活性分析。这些研究表明，通过在托普洛尔环上更大的取代来鉴定抗病毒效力，鉴定了高效力所需的取代的关键组分，并且显示细胞毒性与α-羟托洛芬的增加的亲脂性相关。这些数据为进一步优化α-羟托洛芬骨架作为新型HBV RNA酶H抑制剂提供了重要指导。

版权所有©2017. Elsevier B.V.发行。
关键词：

抗病毒; HBV;定量构效关系;核糖核酸酶H; Tropolones

结论：
    28633989
DOI：
    10.1016 / j.antiviral.2017.06.014