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A Triazinone Derivative Inhibits HIV‐1 Replication by Interfering with Reverse Transcriptase Activity
Author(s) -
Urano Emiko,
Miyauchi Kosuke,
Kojima Yoko,
Hamatake Makiko,
Ablan Sherimay D.,
Fudo Satoshi,
Freed Eric O.,
Hoshino Tyuji,
Komano Jun
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600375
Subject(s) - reverse transcriptase , efavirenz , virology , nucleotidyltransferase , biology , reverse transcriptase inhibitor , docking (animal) , resistance mutation , viral replication , drug resistance , virus , stereochemistry , chemistry , rna , medicine , microbiology and biotechnology , biochemistry , sida , viral load , gene , viral disease , nursing , antiretroviral therapy
A novel HIV‐1 inhibitor, 6‐( tert ‐butyl)‐4‐phenyl‐4‐(trifluoromethyl)‐1 H ,3 H ‐1,3,5‐triazin‐2‐one (compound 1 ), was identified from a compound library screened for the ability to inhibit HIV‐1 replication. EC 50 values of compound 1 were found to range from 107.9 to 145.4 n m against primary HIV‐1 clinical isolates. In in vitro assays, HIV‐1 reverse transcriptase (RT) activity was inhibited by compound 1 with an EC 50 of 4.3 μ m . An assay for resistance to compound 1 selected a variant of HIV‐1 with a RT mutation (RT L100I ); this frequently identified mutation confers mild resistance to non‐nucleoside RT inhibitors (NNRTIs). A recombinant HIV‐1 bearing RT L100I exhibited a 41‐fold greater resistance to compound 1 than the wild‐type virus. Compound 1 was also effective against HIV‐1 with RT K103N , 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 RT K103 than that of efavirenz. Compound 1 is a novel NNRTI with a unique drug‐resistance profile.