3-Hydroxypyrimidine-2,4-Diones as Novel Hepatitis B Virus Antivirals Targeting the Viral Ribonuclease H

Andrew D Huber; Eleftherios Michailidis; Jing Tang; Maritza N Puray-Chavez; Maria Boftsi; Jennifer J Wolf; Kelsey N Boschert; Megan A Sheridan; Maxwell D Leslie; Karen A Kirby; Kamalendra Singh; Hiroaki Mitsuya; Michael A Parniak; Zhengqiang Wang; Stefan G Sarafianos

doi:10.1128/AAC.00245-17

3-Hydroxypyrimidine-2,4-Diones as Novel Hepatitis B Virus Antivirals Targeting the Viral Ribonuclease H

Antimicrob Agents Chemother. 2017 May 24;61(6):e00245-17. doi: 10.1128/AAC.00245-17. Print 2017 Jun.

Authors

Andrew D Huber^{1

2}, Eleftherios Michailidis^{1

3}, Jing Tang⁴, Maritza N Puray-Chavez^{1

3}, Maria Boftsi^{1

2}, Jennifer J Wolf^{1

3}, Kelsey N Boschert^{1

3}, Megan A Sheridan^{1

5}, Maxwell D Leslie^{1

3}, Karen A Kirby^{1

3}, Kamalendra Singh^{1

3}, Hiroaki Mitsuya^{6

7

8}, Michael A Parniak⁹, Zhengqiang Wang⁴, Stefan G Sarafianos^{10

3

5}

Affiliations

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 sarafianoss@missouri.edu.

Abstract

Hepatitis B virus (HBV) RNase H (RNH) is an appealing therapeutic target due to its essential role in viral replication. RNH inhibitors (RNHIs) could help to 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.

Keywords: RNase H; antiviral agents; hepatitis B virus.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / pharmacology*
Hepatitis B virus / drug effects
Hepatitis B virus / genetics*
Humans
Ribonuclease H / genetics
Ribonuclease H / metabolism*
Virus Replication / drug effects
Virus Replication / genetics

Substances

Antiviral Agents
Ribonuclease H

Abstract

Publication types

MeSH terms

Substances

Grants and funding