G-quadruplexes as targets for drug design.
G-quadruplexes are a family of secondary DNA structures formed in the presence of monovalent cations that consist of four-stranded structures in which Hoogsteen base-pairing stabilizes G-tetrad structures. These structures are proposed to exist in vivo, although direct confirmatory evidence is lacking. Guanine-rich regions of DNA capable of forming G-quadruplex structures are found in a variety of chromosomal regions, including telomeres and promoter regions of DNA. In this review, we describe the design of three separate groups of G-quadruplex-interactive compounds and their interaction with G-quadruplex DNA. Using the first group of compounds (anthraquinones), we describe experiments that provide the proof of concept that a G-quadruplex is required for inhibition of telomerase. Using the second group of compounds (perylenes), we describe the structure of a G-quadruplex-ligand complex and its effect on the dynamics of formation and enzymatic unwinding of the quadruplex. For the third group of compounds (porphyrins), we describe the experiments that relate the biological effects to their interactions with G-quadruplexes.
Hurley
L H
LH
Drug Dynamics Institute, The University of Texas, Austin, TX, USA. dg-dna@mail.utexas.edu
Wheelhouse
R T
RT
Sun
D
D
Kerwin
S M
SM
Salazar
M
M
Fedoroff
O Y
OY
Han
F X
FX
Han
H
H
Izbicka
E
E
Von Hoff
D D
DD
D001483:Base Sequence; D001665:Binding Sites; D002455:Cell Division; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000378:metabolism; D006147:Guanine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010569:Perylene / Q000378:metabolism; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D008024:Ligands; D010569:Perylene; D006147:Guanine; D019098:Telomerase