Antimicrob Agents Chemother. 2017 Mar 20. pii: AAC.00245-17. doi: 10.1128/AAC.00245-17. [Epub ahead of print]
3-hydroxypyrimidine-2,4-diones as novel hepatitis B virus antivirals targeting the viral ribonuclease H.
Huber AD1,2, Michailidis E1,3, Tang J4, Puray-Chavez MN1,3, Boftsi M1,2, Wolf JJ1,3, Boschert KN1,3, Sheridan MA1,5, Leslie MD1,3, Kirby KA1,3, Singh K1,3, Mitsuya H6,7,8, Parniak MA9, Wang Z4, Sarafianos SG10,3,5.
Author information
1 Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.
2 Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, USA.
3 Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA.
4 Center for Drug Design, University of Minnesota, Minneapolis, Minnesota, USA.
5 Department of Biochemistry, University of Missouri, Columbia, Missouri, USA.
6 Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Biomedical Sciences, Kumamoto, Japan.
7 Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan.
8 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
9 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
10 Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA [email protected].
Abstract
Hepatitis B virus (HBV) ribonuclease H (RNH) is an appealing therapeutic target due to its essential role in viral replication. RNH inhibitors (RNHIs) could help more effectively control HBV infections. Here, we report 3-hydroxypyrimidine-2,4-diones as novel HBV RNHIs with antiviral activity. We synthesized and tested 52 analogs and found 4 that inhibit HBV RNH activity in infected cells. Importantly, 2 of these compounds inhibited HBV replication in the low micromolar range.
1美国密苏里州密苏里大学克里斯托弗·邦德生命科学中心。
2密苏里大学兽医病理学系,哥伦比亚,密苏里州,美国。
3美国密苏里州密苏里大学医学院分子微生物与免疫学系。
4明尼苏达大学药物设计中心,明尼苏达州明尼阿波利斯,美国。
5美国密苏里州密苏里大学生物化学系。
熊本大学生物医学研究生院,日本熊本市6个传染病与血液学系。
日本东京全国卫生和医学国家中心临床科学中心7。
8实验性病毒科,艾滋病毒和艾滋病恶性分支,国家癌症研究所,国立卫生研究院,Bethesda,马里兰州,美国。
美国宾夕法尼亚州匹兹堡匹兹堡大学医学院微生物与分子遗传学系9。
10 Christopher S. Bond生命科学中心,密苏里大学,哥伦比亚,密苏里州,美国[email protected]。
抽象
乙型肝炎病毒(HBV)核糖核酸酶H(RNH)由于其在病毒复制中的重要作用,是一个吸引人的治疗靶点。 RNH抑制剂(RNHI)可以帮助更有效地控制HBV感染。在这里,我们报告3-羟基嘧啶-2,4-二氢es es as as as as。。。。。。。。。。。。。。我们合成并测试了52个类似物,发现4个在感染细胞中抑制HBV RNH活性。重要的是,其中2种化合物在低微摩尔范围内抑制HBV复制。