Helical foldamers as selective G-quadruplex ligands

We investigated the G-quadruplex binding selectivity of short aromatic oligoamide helical foldamers comprising quinoline (Q) and pyridine (P) units. We found that the foldamers prefer parallel G-quadruplex structures, especially when the external G-quartets are sterically accessible. A crystal structure of the tetramer QQPQ with the parallel G-quadruplex formed by dTGGGTTGGGTTGGGTTGGGT shows two quinoline subunits interacting with an external G-quartet through π-stacking, and solution NMR confirms that the foldamer targets the 3’ and 5’ ends of this G-quadruplex. Foldamers can also selectively target sequence variants of the telomeric sequences containing adenine-to-thymine mutation in the loops. The conformational selectivity of foldamers originates from the bulkiness of oligomers with four or more subunits, which imposes steric restrictions on G-quadruplex binding. The flexibility provided by the pyridine subunits was also key to improve affinity. Mixed quinoline-pyridine foldamers are thus a promising class of selective G-quadruplex ligands, and their unique modular scaffold offers new avenues to further improve their affinity and selectivity.