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

1 Citation (Scopus)

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)
JournalChemical Biology and Drug Design
DOIs
StateAccepted/In press - 2016

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Transcription
Viruses
Reverse Transcription
HIV-1
Molecules
Tropics
Murine Leukemia Viruses
Capsid
RNA-Directed DNA Polymerase
HIV Infections
Bovine Immunodeficiency Virus
Bearings (structural)
Equine infectious anemia virus
Feline Immunodeficiency Virus
Moloney murine leukemia virus
Nevirapine
Simian Immunodeficiency Virus
HIV-2
T-cells
Retroviridae

Keywords

  • Antiviral drug
  • Capsid
  • HIV-1
  • L100
  • NNRTI
  • Reverse transcription

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Opp, S., Fricke, T., Shepard, C., Kovalskyy, D., Bhattacharya, A., Herkules, F., ... Diaz-Griffero, F. (Accepted/In press). The small-molecule 3G11 inhibits HIV-1 reverse transcription. Chemical Biology and Drug Design. https://doi.org/10.1111/cbdd.12886

The small-molecule 3G11 inhibits HIV-1 reverse transcription. / Opp, Silvana; Fricke, Thomas; Shepard, Caitlin; Kovalskyy, Dmytro; Bhattacharya, Akash; Herkules, Frank; Ivanov, Dmitri N.; Kim, Baek; Valle-Casuso, Jose; Diaz-Griffero, Felipe.

In: Chemical Biology and Drug Design, 2016.

Research output: Contribution to journalArticle

Opp, S, Fricke, T, Shepard, C, Kovalskyy, D, Bhattacharya, A, Herkules, F, Ivanov, DN, Kim, B, Valle-Casuso, J & Diaz-Griffero, F 2016, 'The small-molecule 3G11 inhibits HIV-1 reverse transcription', Chemical Biology and Drug Design. https://doi.org/10.1111/cbdd.12886
Opp S, Fricke T, Shepard C, Kovalskyy D, Bhattacharya A, Herkules F et al. The small-molecule 3G11 inhibits HIV-1 reverse transcription. Chemical Biology and Drug Design. 2016. https://doi.org/10.1111/cbdd.12886
Opp, Silvana ; Fricke, Thomas ; Shepard, Caitlin ; Kovalskyy, Dmytro ; Bhattacharya, Akash ; Herkules, Frank ; Ivanov, Dmitri N. ; Kim, Baek ; Valle-Casuso, Jose ; Diaz-Griffero, Felipe. / The small-molecule 3G11 inhibits HIV-1 reverse transcription. In: Chemical Biology and Drug Design. 2016.
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AU - Bhattacharya, Akash

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AU - Diaz-Griffero, Felipe

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AB - 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.

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