A Novel Platform to Investigate G-quadruplex and Ligand Interactions

A collaborative research of the scientists from United States, United Kingdom and Japan has introduced a novel platform to investigate the binding interactions between human telomeric G-quadruplexes and small molecule ligands at single molecule level. This research work has been recently published in Nature Chemistry (link: http://www.nature.com/nchem/journal/v3/n10/pdf/nchem.1126.pdf) which is one of the most reputed Journals in the related field. 

G-quadruplexes are four-stranded nucleic acid secondary structures formed by the guanine rich DNA and RNA sequences. The telomere is one of the critical parts of the eukaryotic chromosomes including those of humans which has propensity to form G-quadruplexes. Telomeres play a vital role in aging and cancer. In normal cells telomere is shortened each time when a cell divides and finally leads to the programmed death of the cell. However in most of the cancer cells, telomere length is maintained because of the over expression of an enzyme called telomerase. The telomerase acts on the telomere and extends its length which makes the cell immortal causing cancer.  The telomeric G-quadruplexes have been proposed to play an important role in the maintenance of telomere because quadruplex structures are not extended by the telomerase. The small molecule ligands have been demonstrated to bind to telomeric G-quadruplexes and suppress telomerase activity. This fact has begun the expansion of telomeric G-quadruplexes into potential therapeutic targets for cancer treatment. Therefore understanding the kinetic, thermodynamic, and mechanical properties of small molecule binding to these structures is important but the classical ensemble assays are unable to measure these properties simultaneously. This novel platform provides the all information at once.

The single molecule assay employs a telomeric G-quadruplex structure to evaluate its interaction with small-molecule ligands in a laser tweezers instrument. Using a force based single-molecule technique, it has been shown that ligand not only promotes the folding of human telomeric G-quadruplex but also increases its mechanical stability. This platform simplifies the dissociation constant assay without the requirement for ligand or receptor titration and offers a general platform that can be applied to other biologically relevant ligand-receptor systems. 

According to Deepak Koirala, a lead author of the paper from Nepal and PhD student of Department of Chemistry and Biochemistry at Kent State University, USA, this study highlights G-quadruplexes that are important dynamic structures involved in the mechanism of telomere elongation by the action of the enzyme complex telomerase. He adds "the mechanical information acquired by this system could provide novel perspectives for drug testing and design in the future".