乙型肝炎病毒核糖核酸酶H抑制剂（一类新的复制拮抗剂）在F

StephenW

Antiviral Res. 2017 Nov 9. pii: S0166-3542(17)30532-6. doi: 10.1016/j.antiviral.2017.11.008. [Epub ahead of print]
Efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice.Long KR1, Lomonosova E2, Li Q3, Ponzar NL4, Villa JA5, Touchette E6, Rapp S7, Liley RM8, Murelli RP9, Grigoryan A10, Buller RM11, Wilson L12, Bial J13, Sagartz JE14, Tavis JE15.
Author information
1Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: [email protected].2Department of Molecular Microbiology and Immunology & the Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: [email protected].3Department of Molecular Microbiology and Immunology & the Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: [email protected].4Department of Molecular Microbiology and Immunology & the Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: [email protected].5Department of Molecular Microbiology and Immunology & the Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: [email protected].6Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: [email protected].7Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: [email protected].8Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: [email protected].9Brookyln College, City University of New York, NY 11210, USA. Electronic address: [email protected].10Brookyln College, City University of New York, NY 11210, USA. Electronic address: [email protected].11Department of Molecular Microbiology and Immunology & the Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: [email protected].12Yecuris Corporation, P.O. Box 4645, Tualatin, OR 97062, USA. Electronic address: [email protected].13Yecuris Corporation, P.O. Box 4645, Tualatin, OR 97062, USA. Electronic address: [email protected].14Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: [email protected].15Department of Molecular Microbiology and Immunology & the Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: [email protected].

AbstractChronic hepatitis B virus infection cannot be cured by current therapies, so new treatments are urgently needed. We recently identified novel inhibitors of the hepatitis B virus ribonuclease H that suppress viral replication in cell culture. Here, we employed immunodeficient FRG KO mice whose livers had been engrafted with primary human hepatocytes to ask whether ribonuclease H inhibitors can suppress hepatitis B virus replication in vivo. Humanized FRG KO mice infected with hepatitis B virus were treated for two weeks with the ribonuclease H inhibitors #110, an α-hydroxytropolone, and #208, an N-hydroxypyridinedione. Hepatitis B virus viral titers and S and e antigen plasma levels were measured. Treatment with #110 and #208 caused significant reductions in plasma viremia without affecting hepatitis B virus S or e antigen levels, and viral titers rebounded following treatment cessation. This is the expected pattern for inhibitors of viral DNA synthesis. Compound #208 suppressed viral titers of both hepatitis B virus genotype A and C isolates. These data indicate that Hepatitis B virus replication can be suppressed during infection in an animal by inhibiting the viral ribonuclease H, validating the ribonuclease H as a novel target for antiviral drug development.

Copyright © 2017. Published by Elsevier B.V.

KEYWORDS: Antivirals; Chimeric mice; FRG; HBV; RNaseH

PMID:29129708DOI:10.1016/j.antiviral.2017.11.008

StephenW

抗病毒研究2017年11月9日。pii：S0166-3542（17）30532-6。 doi：10.1016 / j.antiviral.2017.11.008。 [电子版提前打印]
乙型肝炎病毒核糖核酸酶H抑制剂（一类新的复制拮抗剂）在FRG人类肝脏嵌合体小鼠中的功效。
Long KR1，Lomonosova E2，Li Q3，Ponzar NL4，Villa JA5，Touchette E6，Rapp S7，Liley RM8，Murelli RP9，Grigoryan A10，Buller RM11，Wilson L12，Bial J13，Sagartz JE14，Tavis JE15。
作者信息

1
    Seventh Wave Laboratories LLC，19 Worthington Access Drive，马里兰高地，MO 63043，美国。电子地址：[email protected]。
2
    圣路易斯大学医学院分子微生物学与免疫学系和圣路易斯大学肝脏中心，美国密苏里州圣路易斯S.S.大道1100号，邮编：63104。电子地址：[email protected]。
3
    圣路易斯大学医学院分子微生物学与免疫学系和圣路易斯大学肝脏中心，美国密苏里州圣路易斯S.S.大道1100号，邮编：63104。电子地址：[email protected]。
4
    圣路易斯大学医学院分子微生物学和免疫学系和圣路易斯大学肝脏中心，美国密苏里州圣路易斯S.S.大道1100号，邮编：63104。电子地址：[email protected]。
五
    圣路易斯大学医学院分子微生物学和免疫学系和圣路易斯大学肝脏中心，美国密苏里州圣路易斯S.S.大道1100号，邮编：63104。电子地址：[email protected]。
6
    Seventh Wave Laboratories LLC，19 Worthington Access Drive，马里兰高地，MO 63043，美国。电子地址：[email protected]。
7
    Seventh Wave Laboratories LLC，19 Worthington Access Drive，马里兰高地，MO 63043，美国。电子地址：[email protected]。
8
    Seventh Wave Laboratories LLC，19 Worthington Access Drive，马里兰高地，MO 63043，美国。电子地址：[email protected]。
9
    布鲁克林学院，纽约市立大学，纽约州11210，美国。电子地址：[email protected]。
10
    布鲁克林学院，纽约市立大学，纽约州11210，美国。电子地址：[email protected]。
11
    圣路易斯大学医学院分子微生物学与免疫学系和圣路易斯大学肝脏中心，美国密苏里州圣路易斯S.S.大道1100号，邮编：63104。电子地址：[email protected]。
12
    Yecuris Corporation，P.O.美国OR 97062，Tualatin，Box 4645。电子地址：[email protected]。
13
    Yecuris Corporation，P.O.美国OR 97062，Tualatin，Box 4645。电子地址：[email protected]。
14
    Seventh Wave Laboratories LLC，19 Worthington Access Drive，马里兰高地，MO 63043，美国。电子地址：[email protected]。
15
    圣路易斯大学医学院分子微生物学与免疫学系和圣路易斯大学肝脏中心，美国密苏里州圣路易斯S.S.大道1100号，邮编：63104。电子地址：[email protected]。

抽象

目前的治疗方法不能治愈慢性乙型肝炎病毒感染，所以迫切需要新的治疗方法。我们最近鉴定了乙型肝炎病毒核糖核酸酶H的新型抑制剂，其抑制病毒在细胞培养物中的复制。在这里，我们雇用免疫缺陷的FRG KO小鼠，其肝脏已经移植了原代人类肝细胞，询问核糖核酸酶H抑制剂是否可以抑制体内乙型肝炎病毒的复制。用乙型肝炎病毒感染的人源化FRG KO小鼠用核糖核酸酶H抑制剂＃110（一种α-羟基维生素）和＃208（一种N-羟基吡啶二酮）处理两周。测量乙型肝炎病毒病毒滴度和S和e抗原血浆水平。治疗＃110和＃208导致血浆病毒血症显着降低，而不影响乙型肝炎病毒S或E抗原水平，病毒滴度在治疗停止后反弹。这是病毒DNA合成抑制剂的预期模式。化合物＃208抑制乙型肝炎病毒基因型A和C分离株的病毒滴度。这些数据表明，通过抑制病毒核糖核酸酶H，可以在动物感染过程中抑制乙型肝炎病毒的复制，从而证实核糖核酸酶H是抗病毒药物开发的新靶点。

版权所有©2017. Elsevier B.V.
关键词：

抗病毒药物;嵌合小鼠; FRG; HBV;核糖核酸酶H

结论：
    29129708
DOI：
    10.1016 / j.antiviral.2017.11.008