title: Telomestatin, a potent telomerase inhibitor that interacts quite specifically with the human telomeric intramolecular g-quadruplex.
abstract: Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor. The structural similarity between telomestatin and a G-tetrad suggested to us that the telomerase inhibition might be due to its ability either to facilitate the formation of or trap out preformed G-quadruplex structures, and thereby sequester single-stranded d[T(2)AG(3)](n) primer molecules required for telomerase activity. Significantly, telomestatin appears to be a more potent inhibitor of telomerase (5 nM) than any of the previously described G-quadruplex-interactive molecules. In this communication we provide the first experimental evidence that telomestatin selectively facilitates the formation of or stabilizes intramolecular G-quadruplexes, in particular, that produced from the human telomeric sequence d[T(2)AG(3)](4). A simulated annealing (SA) docking approach was used to study the binding interactions of telomestatin with the intramolecular antiparallel G-quadruplex structure. Each intramolecular G-quadruplex molecule was found to bind two telomestatin molecules (unpublished results). A 2:1 model for the telomestatin bound in the external stacking mode in an energy minimized complex with the human telomeric basket-type G-quadruplex was constructed. Our observation that a G-quadruplex-interactive molecule without significant groove interactions is able to reorient in a G-quadruplex structure proints to the importance of core interaction with an asymmetric G-quadruplex structure in producing selective binding. Furthermore, the G-quadruplex interactions of telomestatin are more selective for the intramolecular structure in contrast to other G-quadruplex-interactive agents, such as TMPyP4.
authors.affiliation: College of Pharmacy, Arizona Cancer Center, Department of Chemistry, The University of Arizona, Tucson, Arizona 85721, USA.
authors.forename: Mu-Yong
authors.initials: MY
authors.lastname: Kim
authors.forename: Hariprasad
authors.initials: H
authors.lastname: Vankayalapati
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shin-Ya
authors.forename: Konstanty
authors.initials: K
authors.lastname: Wierzba
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Hurley
mesh_terms: D004247:DNA / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006147:Guanine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation / Q000187:drug effects; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D012091:Repetitive Sequences, Nucleic Acid; D013379:Substrate Specificity; D019098:Telomerase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D010080:Oxazoles; C431888:telomestatin; D006147:Guanine; D004247:DNA; D019098:Telomerase