A Dynamic G-Quadruplex Region Regulates the HIV-1 Long Terminal Repeat Promoter
- 18 July 2013
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 56 (16), 6521-6530
- https://doi.org/10.1021/jm400914r
Abstract
G-Quadruplexes, noncanonical nucleic acid structures, act as silencers in the promoter regions of human genes; putative G-quadruplex forming sequences are also present in promoters of other mammals, yeasts, and prokaryotes. Here we show that also the HIV-1 LTR promoter exploits G-quadruplex-mediated transcriptional regulation with striking similarities to eukaryotic promoters and that treatment with a G-quadruplex ligand inhibits HIV-1 infectivity. Computational analysis on 953 HIV-1 strains substantiated a highly conserved G-rich sequence corresponding to Sp1 and NF-κB binding sites. Biophysical/biochemical analysis proved that two mutually exclusive parallel-like intramolecular G-quadruplexes, stabilized by small molecule ligands, primarily fold in this region. Mutations disrupting G-quadruplex formation enhanced HIV promoter activity in cells, whereas treatment with a G-quadruplex ligand impaired promoter activity and displayed antiviral effects. These findings disclose the possibility of inhibiting the HIV-1 LTR promoter by G-quadruplex-interacting small molecules, providing a new pathway to development of anti-HIV-1 drugs with unprecedented mechanism of action.This publication has 47 references indexed in Scilit:
- Tertiary DNA Structure in the Single-Stranded hTERT Promoter Fragment Unfolds and Refolds by Parallel Pathways via Cooperative or Sequential EventsJournal of the American Chemical Society, 2012
- Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?Nature Reviews Drug Discovery, 2011
- G-Quadruplex-Binding Benzo[a]phenoxazines Down-Regulate c-KIT Expression in Human Gastric Carcinoma CellsJournal of the American Chemical Society, 2011
- Molecular Cloning of the Human Platelet-Derived Growth Factor Receptor β (PDGFR-β) Promoter and Drug Targeting of the G-Quadruplex-Forming Region To Repress PDGFR-β ExpressionBiochemistry, 2010
- HIV-1 Nef Dimerization Is Required for Nef-Mediated Receptor Downregulation and Viral ReplicationJournal of Molecular Biology, 2009
- Chemical Library Screens Targeting an HIV-1 Accessory Factor/Host Cell Kinase Complex Identify Novel Antiretroviral CompoundsACS Chemical Biology, 2009
- Formation of a Unique End-to-End Stacked Pair of G-Quadruplexes in the hTERT Core Promoter with Implications for Inhibition of Telomerase by G-Quadruplex-Interactive LigandsJournal of the American Chemical Society, 2009
- Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regionsBiochimie, 2008
- Using circular dichroism collected as a function of temperature to determine the thermodynamics of protein unfolding and binding interactionsNature Protocols, 2006
- G-quadruplexes in promoters throughout the human genomeNucleic Acids Research, 2006