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A Triazinone Derivative Inhibits HIV-1 Replication by Interfering with Reverse Transcriptase Activity

  1. Author:
    Urano, E.
    Miyauchi, K.
    Kojima, Y.
    Hamatake, M.
    Ablan, S. D.
    Fudo, S.
    Freed, E. O.
    Hoshino, T.
    Komano, J.

  2. Author Address

    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. RIKEN Center for Integrative Medical Sciences, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa, 230-0045, Japan. Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, 3-69, Nakamachi, 1-chome, Higashinari-ku, Osaka, 537-0025, Japan. Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba, 263-8522, Japan. 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.
    1. Year: 2016
    2. Date: 19-Oct
    3. Epub Date: 10/21/2016
  2. Journal: Chemmedchem
    1. 11
    2. 20
    3. Pages: 2320-2326
  4. Type of Article: Article
  5. ISSN: 1860-7179
  1. 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. EC50 values 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 EC50 of 4.3 mum. 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 RTL100I exhibited 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 RTK103 than that of efavirenz. Compound 1 is a novel NNRTI with a unique drug-resistance profile.

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External Sources

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  2. DOI: 10.1002/cmdc.201600375
  3. PMID: 27634404
  4. View record in Web of Science®
  5. WOS: 000387392800008

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