title: A Triazinone Derivative Inhibits HIV-1 Replication by Interfering with Reverse Transcriptase Activity.
abstract: A novel HIV-1 inhibitor, 6-(tert-butyl)-4-phenyl-4-(trifluoromethyl)-1H,3H-1,3,5-triazin-2-one (compound 1), was identified from a compound library screened for the ability to inhibit HIV-1 replication. EC50values of compound 1 were found to range from 107.9 to 145.4 nm against primary HIV-1 clinical isolates. In in vitro assays, HIV-1 reverse transcriptase (RT) activity was inhibited by compound 1 with an EC50of 4.3 μm. An assay for resistance to compound 1 selected a variant of HIV-1 with a RT mutation (RTL100I); this frequently identified mutation confers mild resistance to non-nucleoside RT inhibitors (NNRTIs). A recombinant HIV-1 bearing RTL100Iexhibited a 41-fold greater resistance to compound 1 than the wild-type virus. Compound 1 was also effective against HIV-1 with RTK103N, one of the major mutations that confers substantial resistance to NNRTIs. Computer-assisted docking simulations indicated that compound 1 binds to the RT NNRTI binding pocket in a manner similar to that of efavirenz; however, the putative compound 1 binding site is located further from RTK103than that of efavirenz. Compound 1 is a novel NNRTI with a unique drug-resistance profile.
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.|The Virus-Cell Interaction Section, HIV Dynamics and Replication Program, National Cancer Institute, Frederick, MD, 21701, USA.
authors.forename: Emiko
authors.initials: E
authors.lastname: Urano
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.|RIKEN Center for Integrative Medical Sciences, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa, 230-0045, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Miyauchi
authors.affiliation: Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, 3-69, Nakamachi, 1-chome, Higashinari-ku, Osaka, 537-0025, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Hamatake
authors.affiliation: The Virus-Cell Interaction Section, HIV Dynamics and Replication Program, National Cancer Institute, Frederick, MD, 21701, USA.
authors.forename: Sherimay D
authors.initials: SD
authors.lastname: Ablan
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba, 263-8522, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fudo
authors.affiliation: The Virus-Cell Interaction Section, HIV Dynamics and Replication Program, National Cancer Institute, Frederick, MD, 21701, USA.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Freed
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba, 263-8522, Japan.
authors.forename: Tyuji
authors.initials: T
authors.lastname: Hoshino
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan. komano@nnh.hops.go.jp.|Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, 3-69, Nakamachi, 1-chome, Higashinari-ku, Osaka, 537-0025, Japan. komano@nnh.hops.go.jp.|Department of Clinical Laboratory, Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya, 460-0001, Japan. komano@nnh.hops.go.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Komano
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D014227:Triazines; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: HIV-1; NNRTI; antiviral agents; drug resistance; reverse transcriptase; triazinones