Solution Structure of an Intramolecular (3 + 1) Human Telomeric G-Quadruplex Bound to a Telomestatin Derivative

Abstract

Guanine-rich human telomeric DNA can adopt secondary structures known as G-quadruplexes, which can be targeted by small molecules to achieve anticancer effects. So far, the structural information on complexes between human telomeric DNA and ligands is limited to the parallel G-quadruplex conformation, despite the high structural polymorphism of human telomeric G-quadruplexes. No structure has been yet resolved for the complex with telomestatin, one of the most promising G-quadruplex-targeting anticancer drug candidates. Here we present the first high-resolution structure of the complex between an intramolecular (3 + 1) human telomeric G-quadruplex and a telomestatin derivative, the macrocyclic hexaoxazole L2H2-6M(2)OTD. This compound is observed to interact with the G-quadruplex through π-stacking and electrostatic interactions. This structural information provides a platform for the design of topology-specific G-quadruplex-targeting compounds and is valuable for the development of new potent anticancer drugs.

Selectivity of major isoquinoline alkaloids from Chelidonium majus towards telomeric G-quadruplex: A study using a transition-FRET (t-FRET) assay

“…G4 structure stabilization was recorded for sanguinarine in a considerably stronger extent than berberine. The ∆T m of F21T varied considerably in presence of these three alkaloids, although molecular modeling methods suggest almost the similar mode of interactions and comparable binding energies in the hybrid 3+1 topology [64]. Non-electrostatic interactions in the binding of small molecules to G4 are preferable for telomerase inhibition under physiological conditions [60].…”

“…The hybrid 3+1 topology of intramolecular telomeric quadruplex (PDB id 2MB3) was used as the starting point to study G4-ligand interactions [64]. The docking and molecular dynamics protocol was adapted from Ohnmacht et al [39].…”

Human telomerase inhibitors from microbial source

“…More recently a series of macrocyclic molecules (telomestatin analogues) have been developed, with improved features over telomestatin parental structure (Granzhan et al 2010). Macrocyclic hexaoxazole L2H2-6 M (2) OTD is such a derivative of telomestatin which interact with G-quadruplex by p-stacking and electrostatic interactions (Chung et al 2013) telomestatin is currently under clinical trials (Kim and McAlpine 2013). Daunomycin (Fig.…”

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

“…Finally, by combining the structural aspects of T4 and Telomestatin, Nagasawa et al made T9, which had a better potency in stabilizing the G-quadruplex than the one of T4 [67]. Resolving the structure of a complex formed between T9 and human telomeric G-quadruplex DNA, Nagasawa et al concluded that the analogue interacted with the G-quadruplex via p-stacking and electrostatic interactions [68].…”