Abstract
A single G-quadruplex forming sequence from the human telomere can adopt six distinct topologies that are inter-convertible under physiological conditions. This presents challenges to design ligands that show selectivity and specificity towards a particular conformation. Additional complexity is introduced in differentiating multimeric G-quadruplexes over monomeric species, which would be able to form in the single-stranded 3′ ends of telomeres. A few ligands have been reported that bind to dimeric quadruplexes, but their preclinical pharmacological evaluation is limited. Using multidisciplinary approaches, we identified a novel quinoline core ligand, BMPQ-1, which bound to human telomeric G-quadruplex multimers over monomeric G-quadruplexes with high selectivity, and induced the formation of G-quadruplex DNA along with the related DNA damage response at the telomere. BMPQ-1 reduced tumor cell proliferation with an IC50 of ∼1.0 μM and decreased tumor growth rate in mouse by half. Biophysical analysis using smFRET identified a mixture of multiple conformations coexisting for dimeric G-quadruplexes in solution. Here, we showed that the titration of BMPQ-1 shifted the conformational ensemble of multimeric G-quadruplexes towards (3+1) hybrid-2 topology, which became more pronounced as further G-quadruplex units are added.
Highlights
Four repeats of the human telomeric sequence, (TTAGGG)n is able to fold into a monomeric G-quadruplex structure [1,2]
These compounds were evaluated for their ability to bind to TTA45 by Fluorescence Resonance Energy Transfer (FRET) assay (Supplementary Tables S1 and S2) [47]
Compounds 21–38 were purchased to study their binding with TTA45 by FRET (Supplementary Table S3)
Summary
Four repeats of the human telomeric sequence, (TTAGGG)n is able to fold into a monomeric (single unit) G-quadruplex structure [1,2]. The central unit of a G-quadruplex is a series of co-planar array of guanines, held together by Hoogsteen hydrogen bonds and stacked on top of another, called the G-quartet stem [3,4,5]. The flanking sequence TTA, contributes to the formation of the loops.
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