Topology of a DNA G‑Quadruplex Structure Formed in the HIV‑1 Promoter: A Potential Target for Anti-HIV Drug Development

• Published in: Journal of the American Chemical Society Vol. 136; no. 14; pp. 5249 - 5252
• Main Authors: Amrane, Samir, Kerkour, Abdelaziz, Bedrat, Amina, Vialet, Brune, Andreola, Marie-Line, Mergny, Jean-Louis
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 09.04.2014
• Subjects: 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; Life Sciences; Ligands; Microbiology and Parasitology; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - genetics; Structure-Activity Relationship
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja501500c

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.