title: 3-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations.
abstract: Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochemical evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochemical studies showed the two subtypes with an N-1 methyl group (9 and 10) inhibited RNase H in low micromolar range without significantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype 11 inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Tang
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania 15219, United States.
authors.forename: Eva
authors.initials: E
authors.lastname: Nagy
authors.affiliation: Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania 15219, United States.
authors.forename: Lena
authors.initials: L
authors.lastname: Miller
authors.affiliation: Department of Molecular Microbiology and Immunology and Department of Biochemistry, University of Missouri School of Medicine , Christopher S. Bond Life Sciences Center, Columbia, Missouri 65211, United States.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Kirby
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Bulan
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Molecular Microbiology and Immunology and Department of Biochemistry, University of Missouri School of Medicine , Christopher S. Bond Life Sciences Center, Columbia, Missouri 65211, United States.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Sarafianos
authors.affiliation: Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania 15219, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Parniak
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Zhengqiang
authors.initials: Z
authors.lastname: Wang
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D016133:Polymerase Chain Reaction; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D054309:Ribonuclease H, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; D054303:HIV Reverse Transcriptase; D012321:DNA-Directed RNA Polymerases; D054309:Ribonuclease H, Human Immunodeficiency Virus