Identification of Novel Quadruplex Ligands from Small Molecule Libraries by FRET‐Based High‐Throughput Screening

Abstract

Quadruple alliance: By performing a screen for binders of the human telomeric repeat sequence with small molecule libraries, the principle of which is outlined in the scheme, we have identified novel compounds that stabilise the G quadruplex structure. Some of these could be suitable leads for further optimisation as potent and selective quadruplex ligands.

Screening of a Chemical Library by HT-G4-FID for Discovery of Selective G-quadruplex Binders

“…There is an increasing interest in high-throughput screening assays [6], among which the Fluorescent Intercalator Displacement (FID) assay has been already used for assessing DNA binding properties of small molecules [7][8][9][10][11]. We developed previously the G4-FID assay in order to determine the affinity of putative G4-DNA ligands together with their selectivity vs. duplex DNA [12][13][14][15].…”

Discovery of new G-quadruplex binding chemotypes

“…A similar chemotype, with a urea group replacing the furan ring, has been reported 23 as having high G4 affinity. These compounds are structurally-simple, conformationally flexible and chemically readily accessible with M Wts <400 Da.…”

Tracking the formation of supramolecular G-quadruplexes via self-assembly enhanced emission

“…Absorption and emission spectroscopies are valuable alternatives that have been applied extensively in the study of supramolecular systems. For example, phenomena such as Förster Resonance Energy Transfer (FRET) 1–3 have enabled studies of precise assemblies 4, 5 while aggregation induced emission (AIE) 6, 7 is more suitable for polymeric or ill-defined aggregates. These and related strategies have opened the door to studies in complex biological environments and the increasing application of supramolecular systems to address problems of biomedical relevance.…”