Anti-HIV-1 activity of the G-quadruplex ligand BRACO-19

J Antimicrob Chemother. 2014 Dec;69(12):3248-58. doi: 10.1093/jac/dku280. Epub 2014 Aug 6.


Objectives: A dynamic G-quadruplex region has been previously shown to form in the long terminal repeat (LTR) promoter of the HIV-1 integrated DNA genome. Inhibition of promoter activity and antiviral effects have been observed when this region was stabilized by BRACO-19, a trisubstituted acridine derivative that binds G-quadruplexes. Here, we aimed at characterizing the antiviral mechanism of action of BRACO-19 by analysing its activity towards a broad range of HIV-1 strains, host cells and infection modes.

Methods: The antiviral activity of BRACO-19 in cell lines and primary cells infected or persistently infected by HIV-1 strains was evaluated at different times post-infection. Virucidal, viral binding, time-dependent and drug-dependent assays were performed to identify the viral target step. Circular dichroism, UV spectroscopy and a reverse transcriptase (RT) stop assay were used to assess RNA G-quadruplex folding and inhibition of RT processing.

Results: Thorough virological assays demonstrated that BRACO-19 acts both at the reverse transcription and the post-integration level during the virus life cycle. This behaviour was rationalized by the observation that a G-quadruplex-forming sequence identical to that of the LTR DNA is present at the 3'-end of the virus RNA genome. Biophysics and biomolecular testing showed that this region has the ability to fold into very stable G-quadruplex structures that are even more stabilized by BRACO-19, therefore inhibiting the reverse transcription process at the template level.

Conclusions: Our findings strongly support the activity of BRACO-19 at the viral G-quadruplex level and therefore strengthen the use of viral G-quadruplexes as new anti-HIV-1 targets.

Keywords: G-quadruplex RNA; antiviral activity; nucleic acid secondary conformation; small molecule; time of addition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acridines / pharmacology*
  • Anti-HIV Agents / pharmacology*
  • G-Quadruplexes / drug effects*
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Inhibitory Concentration 50
  • Microbial Sensitivity Tests
  • Microbial Viability / drug effects
  • Proviruses / drug effects
  • RNA, Viral / drug effects*
  • Reverse Transcription / drug effects


  • Acridines
  • Anti-HIV Agents
  • RNA, Viral
  • BRACO-19