含酰胺的α-羟基营养素作为乙型肝炎病毒复制的抑制剂

StephenW

Antiviral Res. 2020 Mar 23:104777. doi: 10.1016/j.antiviral.2020.104777. [Epub ahead of print]
Amide-containing α-hydroxytropolones as inhibitors of hepatitis B virus replication.
Li Q1, Lomonosova E2, Donlin MJ3, Cao F4, O'Dea A5, Milleson B1, Berkowitz AJ6, Baucom JC7, Stasiak JP8, Schiavone DV9, Abdelmessih RG10, Lyubimova A11, Fraboni AJ12, Bejcek LP13, Villa JA14, Gallicchio E15, Murelli RP16, Tavis JE17.
Author information

1
    Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd, Saint Louis, MO, 63104, USA.
2
    Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd, Saint Louis, MO, 63104, USA. Electronic address: [email protected].
3
    Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1100 S. Grand Blvd, Saint Louis, MO, 63104, USA. Electronic address: [email protected].
4
    John Cochran Division, Department of Veterans Affairs Medical Center, Saint Louis, MO, USA. Electronic address: [email protected].
5
    Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd, Saint Louis, MO, 63104, USA. Electronic address: [email protected].
6
    Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Program in Chemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA. Electronic address: [email protected].
7
    Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Program in Chemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA. Electronic address: [email protected].
8
    Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA. Electronic address: [email protected].
9
    Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Program in Chemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA. Electronic address: [email protected].
10
    Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA. Electronic address: [email protected].
11
    Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA. Electronic address: [email protected].
12
    Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA. Electronic address: [email protected].
13
    Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Program in Chemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA. Electronic address: [email protected].
14
    Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd, Saint Louis, MO, 63104, USA. Electronic address: [email protected].
15
    Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Program in Chemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA; Program in Biochemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA. Electronic address: [email protected].
16
    Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Program in Chemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA; Program in Biochemistry, The Graduate Center of The City University of New York, New York, NY, 11210, USA. Electronic address: [email protected].
17
    Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd, Saint Louis, MO, 63104, USA. Electronic address: [email protected].

Abstract

The Hepatitis B Virus (HBV) ribonuclease H (RNaseH) is a promising but unexploited drug target. Here, we synthesized and analyzed a library of 57 amide-containing α-hydroxytropolones (αHTs) as potential leads for HBV drug development. Fifty percent effective concentrations ranged from 0.31 to 54 μM, with selectivity indexes in cell culture of up to 80. Activity against the HBV RNaseH was confirmed in semi-quantitative enzymatic assays with recombinant HBV RNaseH. The compounds were overall poorly active against human ribonuclease H1, with 50% inhibitory concentrations of 5.1 to >1,000 μM. The αHTs had modest activity against growth of the fungal pathogen Cryptococcus neoformans, but had very limited activity against growth of the Gram - bacterium Escherichia coli and the Gram + bacterium Staphylococcus aureus, indicating substantial selectivity for HBV. A molecular model of the HBV RNaseH templated against the Ty3 RNaseH was generated. Docking the compounds to the RNaseH revealed the anticipated binding pose with the divalent cation coordinating motif on the compounds chelating the two Mn++ ions modeled into the active site. These studies reveal that that amide αHTs can be strong, specific HBV inhibitors that merit further assessment toward becoming anti-HBV drugs.

Copyright © 2020. Published by Elsevier B.V.
KEYWORDS:

Hepatitis B Virus; Molecular modeling; Ribonuclease H; α-Hydroxytropolones

PMID:
    32217151
DOI:
    10.1016/j.antiviral.2020.104777

StephenW

抗病毒水库。 2020年3月23日：104777。 doi：10.1016 / j.antiviral.2020.104777。 [Epub提前发行]
含酰胺的α-羟基营养素作为乙型肝炎病毒复制的抑制剂。
李Q1，罗蒙诺索娃E2，唐林MJ3，曹F4，奥迪A5，米勒森B1，伯科维茨AJ6，鲍科姆JC7，斯塔西亚克JP8，夏沃涅DV9，阿卜杜勒西希RG10，柳比娃娃A11，弗拉博尼AJ12，贝杰西克·加尔奇，比亚迪LP13， Murelli RP16，Tavis JE17。
作者信息

1个
    圣路易斯大学医学院分子微生物学和免疫学系，美国密苏里州圣路易斯1100 S. Grand Blvd，邮编：63104。
2
    圣路易斯大学医学院分子微生物学和免疫学系，美国密苏里州圣路易斯1100 S. Grand Blvd，邮编：63104。电子地址：[email protected]。
3
    爱德华·杜伊斯（Edward A. Doisy），圣路易斯大学医学院生物化学和分子生物学系，美国密苏里州圣路易斯，1100 S. Grand Blvd，63104，美国。电子地址：[email protected]。
4
    美国密苏里州圣路易斯，退伍军人事务医学中心系John Cochran科。电子地址：[email protected]。
5
    圣路易斯大学医学院分子微生物学和免疫学系，美国密苏里州圣路易斯1100 S. Grand Blvd，邮编：63104。电子地址：[email protected]。
6
    纽约城市大学布鲁克林学院化学系，纽约，布鲁克林，11210，美国；化学课程，纽约城市大学研究生中心，纽约，纽约，11210，美国。电子地址：[email protected]。
7
    纽约城市大学布鲁克林学院化学系，纽约，布鲁克林，11210，美国；化学课程，纽约城市大学研究生中心，纽约，纽约，11210，美国。电子地址：[email protected]。
8
    纽约城市大学布鲁克林学院化学系，纽约，布鲁克林，11210，美国。电子地址：[email protected]。
9
    纽约城市大学布鲁克林学院化学系，纽约，布鲁克林，11210，美国；化学课程，纽约城市大学研究生中心，纽约，纽约，11210，美国。电子地址：[url=mailto[email protected]][email protected][/url]。
10
    纽约城市大学布鲁克林学院化学系，纽约，布鲁克林，11210，美国。电子地址：[email protected]。
11
    纽约城市大学布鲁克林学院化学系，纽约，布鲁克林，11210，美国。电子地址：[email protected]。
12
    纽约城市大学布鲁克林学院化学系，纽约，布鲁克林，11210，美国。电子地址：[email protected]。
13
    纽约城市大学布鲁克林学院化学系，纽约，布鲁克林，11210，美国；化学课程，纽约城市大学研究生中心，纽约，纽约，11210，美国。电子地址：[url=mailto[email protected]][email protected][/url]。
14
    圣路易斯大学医学院分子微生物学和免疫学系，美国密苏里州圣路易斯1100 S. Grand Blvd，邮编：63104。电子地址：[email protected]。
15
    纽约城市大学布鲁克林学院化学系，纽约，布鲁克林，11210，美国；纽约城市大学研究生中心化学专业，纽约，纽约，11210；纽约市城市大学研究生中心生物化学专业，纽约，纽约，11210。电子地址：[email protected]。
16
    纽约城市大学布鲁克林学院化学系，纽约，布鲁克林，11210，美国；纽约城市大学研究生中心化学专业，纽约，纽约，11210；纽约市城市大学研究生中心生物化学专业，纽约，纽约，11210。电子地址：[email protected]。
17
    圣路易斯大学医学院分子微生物学和免疫学系，美国密苏里州圣路易斯1100 S. Grand Blvd，邮编：63104。电子地址：[email protected]。

抽象

乙型肝炎病毒（HBV）核糖核酸酶H（RNaseH）是一种有前途但未开发的药物靶标。在这里，我们合成并分析了含有57酰胺的α-羟基对苯二酚（αHTs）库，作为HBV药物开发的潜在先导。 50％的有效浓度范围为0.31至54μM，在细胞培养中的选择性指数高达80。针对HBV RNaseH的活性在重组HBV RNaseH的半定量酶分析中得到了证实。这些化合物总体上对人核糖核酸酶H1的活性较弱，抑制浓度为50％，范围为5.1至>1,000μM。 αHTs对真菌病原体新隐球菌的生长具有适度的活性，但对革兰氏大肠杆菌和金黄色葡萄球菌的生长具有非常有限的活性，表明对HBV有相当大的选择性。生成了针对Ty3 RNaseH模板化的HBV RNaseH的分子模型。将化合物与RNaseH对接后，显示出预期的结合姿势，即化合物上的二价阳离子配位基螯合了被建模为活性位点的两个Mn ++离子。这些研究表明，酰胺αHTs可能是强的，特异性的HBV抑制剂，值得进一步评估，以成为抗HBV药物。

版权所有©2020。由Elsevier B.V.发布。
关键字：

乙型肝炎病毒;分子建模；核糖核酸酶H; α-羟基营养素

PMID：
    32217151
DOI：
    10.1016 / j.antiviral.2020.104777