G-Quadruplex DNA as a Target for Drug Design

Sean   Michael   Kerwin

doi:10.2174/1381612003400849

Abstract

G-rich DNA sequences can adopt unusual four-stranded DNA structures, called G-quadruplex DNA. Variations in the molecularity, topology, strand orientation, and glycosidic conformation of the G-quadruplex DNA provide a diverse array of structures. Although G-quadruplex structures have only been observed in vitro, strong indirect evidence for their existence in vivo comes from the characterization of G-quadruplex DNA binding proteins, helicases, and nucleases. Telomeres are structures on the ends of chromosomes that are required for chromosomal stability. Telomeric DNA contains a single-stranded G-rich DNA overhang, which may adopt a G-quadruplex structure. Telomere shortening has been implicated in cellular senescence. Telomerase is an enzyme which synthesizes the G-rich strand of telomere DNA. Telomerase activity is highly correlated with cancer and may allow cancer cells to escape senescence. Based on these observations, telomerase has been proposed as a potential target for anticancer drug design. The targeting of telomerase is associated with potential problems, including the existence in some cancer cells of telomerase-independent mechanisms for telomere maintenance, and the long delay time between telomerase inhibition and effects on proliferation. One promising approach for inhibiting telomerase involves targeting the G-quadruplex DNA structures thought to be involved in telomere and telomerase function. Compounds that specifically bind G-quadruplex DNA may interact directly with telomeres, in addition to inhibiting telomerase, and produce more immediate antiproliferative effects. The diamidoanthraquinones, porphyrins, and perylene diimides have all been shown to bind G-quadruplex DNA and inhibit telomerase. Most of these compounds also bind double-stranded DNA and are cytotoxic at the concentrations required to inhibit telomerase; however, certain perylene diimides appear to be non-cytotoxic, G-quadruplex selective telomerase inhibitors. Biological characterization of such compounds may provide validation for the concept of the G-quadruplex as a target in drug design.

Keywords: G quadruplex DNA, drug design, tetrahymena, metal Ion Binding, structural diversity, telomerase inhibition, ethidium bromide, diaminoanthraquinones, cytotoxicity, porphyrins, carbocyanines, perylene Diimides, BLM helicase