3-Hydroxypyrimidine-2,4-Diones as Novel Hepatitis B Virus Antivirals Targeting the Viral Ribonuclease H.
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.
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.|Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, USA.
Andrew D
AD
Huber
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.|Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA.
Eleftherios
E
Michailidis
Center for Drug Design, University of Minnesota, Minneapolis, Minnesota, USA.
Jing
J
Tang
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.|Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA.
Maritza N
MN
Puray-Chavez
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.|Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, USA.
Maria
M
Boftsi
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.|Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA.
Jennifer J
JJ
Wolf
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.|Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA.
Kelsey N
KN
Boschert
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.|Department of Biochemistry, University of Missouri, Columbia, Missouri, USA.
Megan A
MA
Sheridan
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.|Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA.
Maxwell D
MD
Leslie
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.|Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA.
Karen A
KA
Kirby
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.|Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA.
Kamalendra
K
Singh
Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Biomedical Sciences, Kumamoto, Japan.|Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan.|Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Hiroaki
H
Mitsuya
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Michael A
MA
Parniak
Center for Drug Design, University of Minnesota, Minneapolis, Minnesota, USA.
Zhengqiang
Z
Wang
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA sarafianoss@missouri.edu.|Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA.|Department of Biochemistry, University of Missouri, Columbia, Missouri, USA.
Stefan G
SG
Sarafianos
D000998:Antiviral Agents / Q000494:pharmacology*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D016914:Ribonuclease H / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
D000998:Antiviral Agents; D016914:Ribonuclease H
RNase H; antiviral agents; hepatitis B virus