The small-molecule 3G11 inhibits HIV-1 reverse transcription

Silvana Opp, Thomas Fricke, Caitlin Shepard, Dmytro Kovalskyy, Akash Bhattacharya, Frank Herkules, Dmitri N. Ivanov, Baek Kim, Jose Valle-Casuso, Felipe Diaz-Griffero

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

The small-molecule 6-(tert-butyl)-4-phenyl-4-(trifluoromethyl)-1H,3H-1,3,5-triazin-2-one (3G11) inhibits HIV-1 replication in the human T cell line MT-2. Here, we showed that 3G11 specifically and potently blocks HIV-1 infection. By contrast, 3G11 did not block other retroviruses such as HIV-2, simian immunodeficiency virus (SIVmac), bovine immunodeficiency virus, feline immunodeficiency virus, equine infectious anemia virus, N-tropic murine leukemia virus, B-tropic murine leukemia virus, and Moloney murine leukemia virus. Analysis of DNA metabolism by real-time PCR revealed that 3G11 blocks the formation of HIV-1 late reverse transcripts during infection prior to the first-strand transfer step. In agreement, an in vitro assay revealed that 3G11 blocks the enzymatic activity of HIV-1 reverse transcriptase as strong as nevirapine. Docking of 3G11 to the HIV-1 reverse transcriptase enzyme suggested a direct interaction between residue L100 and 3G11. In agreement, an HIV-1 virus bearing the reverse transcriptase change L100I renders HIV-1 resistant to 3G11, which suggested that the reverse transcriptase enzyme is the viral determinant for HIV-1 sensitivity to 3G11. Although NMR experiments revealed that 3G11 binds to the HIV-1 capsid, functional experiments suggested that capsid is not the viral determinant for sensitivity to 3G11. Overall, we described a novel non-nucleoside reverse transcription inhibitor that blocks HIV-1 infection.

Original languageEnglish (US)
Pages (from-to)608-618
Number of pages11
JournalChemical Biology and Drug Design
Volume89
Issue number4
DOIs
StatePublished - Apr 1 2017

Keywords

  • HIV-1
  • L100
  • NNRTI
  • antiviral drug
  • capsid
  • reverse transcription

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Opp, S., Fricke, T., Shepard, C., Kovalskyy, D., Bhattacharya, A., Herkules, F., Ivanov, D. N., Kim, B., Valle-Casuso, J., & Diaz-Griffero, F. (2017). The small-molecule 3G11 inhibits HIV-1 reverse transcription. Chemical Biology and Drug Design, 89(4), 608-618. https://doi.org/10.1111/cbdd.12886