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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. 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??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.

SUBMITTER: Urano E

PROVIDER: S-EPMC7754980 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Urano Emiko E Miyauchi Kosuke K Kojima Yoko Y Hamatake Makiko M Ablan Sherimay D SD Fudo Satoshi S Freed Eric O EO Hoshino Tyuji T Komano Jun J

ChemMedChem 20160916 20

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. EC<sub>50</sub> 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 EC<sub>50</sub> of 4.3 μm. An assay for resistance to compound 1 selected a va ...[more]

PMID: 27634404

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Project description:Human immunodeficiency virus type 1 (HIV-1) replication requires reverse transcription of its RNA genome into a double-stranded cDNA copy, which is then integrated into the host cell chromosome. The essential steps of reverse transcription and integration are catalyzed by the viral enzymes reverse transcriptase (RT) and integrase (IN), respectively. In vitro, HIV-1 RT can bind with IN, and the C-terminal domain (CTD) of IN is necessary and sufficient for this binding. To better define the RT-IN interaction, we performed nuclear magnetic resonance (NMR) spectroscopy experiments to map a binding surface on the IN CTD in the presence of RT prebound to a duplex DNA construct that mimics the primer-binding site in the HIV-1 genome. To determine the biological significance of the RT-IN interaction during viral replication, we used the NMR chemical shift mapping information as a guide to introduce single amino acid substitutions of nine different residues on the putative RT-binding surface in the IN CTD. We found that six viral clones bearing such IN substitutions (R231E, W243E, G247E, A248E, V250E, and I251E) were noninfectious. Further analyses of the replication-defective IN mutants indicated that the block in replication took place specifically during early reverse transcription. The recombinant INs purified from these mutants, though retaining enzymatic activities, had diminished ability to bind RT in a cosedimentation assay. The results indicate that the RT-IN interaction is functionally relevant during the reverse transcription step of the HIV-1 life cycle.To establish a productive infection, human immunodeficiency virus type 1 (HIV-1) needs to reverse transcribe its RNA genome to create a double-stranded DNA copy and then integrate this viral DNA genome into the chromosome of the host cell. These two essential steps are catalyzed by the HIV-1 enzymes reverse transcriptase (RT) and integrase (IN), respectively. We have shown previously that IN physically interacts with RT, but the importance of this interaction during HIV-1 replication has not been fully characterized. In this study, we have established the biological significance of the HIV-1 RT-IN interaction during the viral life cycle by demonstrating that altering the RT-binding surface on IN disrupts both reverse transcription and viral replication. These findings contribute to our understanding of the RT-IN binding mechanism, as well as indicate that the RT-IN interaction can be exploited as a new antiviral drug target.

Dataset Information

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

Publications

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

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