Topology of a DNA G-quadruplex structure formed in the HIV-1 promoter: a potential target for anti-HIV drug development

J Am Chem Soc. 2014 Apr 9;136(14):5249-52. doi: 10.1021/ja501500c. Epub 2014 Mar 27.

Abstract

Nucleic acid sequences containing guanine tracts are able to adopt noncanonical four-stranded nucleic acid structures called G-quadruplexes (G4s). These structures are based on the stacking of two or more G-tetrads; each tetrad is a planar association of four guanines held together by eight hydrogen bonds. In this study, we analyzed a conserved G-rich region from HIV-1 promoter that is known to regulate the transcription of the HIV-1 provirus. Strikingly, our analysis of an alignment of 1684 HIV-1 sequences from this region showed a high conservation of the ability to form G4 structures despite a lower conservation of the nucleotide primary sequence. Using NMR spectroscopy, we determined the G4 topology adopted by a DNA sequence from this region (HIV-PRO1: 5' TGGCCTGGGCGGGACTGGG 3'). This DNA fragment formed a stable two G-tetrad antiparallel G4 with an additional Watson-Crick CG base pair. This hybrid structure may be critical for HIV-1 gene expression and is potentially a novel target for anti-HIV-1 drug development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acridines / chemical synthesis
  • Acridines / chemistry
  • Acridines / pharmacology*
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • DNA, Viral / chemistry
  • DNA, Viral / drug effects*
  • DNA, Viral / genetics
  • G-Quadruplexes / drug effects*
  • HIV-1 / chemistry
  • HIV-1 / drug effects*
  • HIV-1 / genetics*
  • Ligands
  • Promoter Regions, Genetic / drug effects*
  • Promoter Regions, Genetic / genetics
  • Structure-Activity Relationship

Substances

  • Acridines
  • Anti-HIV Agents
  • DNA, Viral
  • Ligands
  • BRACO-19