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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.
Copyright © 2017 American Society for Microbiology.
PMID:
28320718
DOI:
10.1128/AAC.00245-17
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