Helical aromatic oligoamide foldamers as selective G-quadruplex ligands

We investigated the G-quadruplex (G4) binding selectivity of short aromatic oligoamide helical foldamers comprising quinoline (Q) and pyridine (P) units. We found that the foldamers bind with 1:1 and 2:1 stoichiometries and prefer parallel G4 structures, especially when the external G-quartets are sterically accessible. A crystal structure of the tetramer QQPQ with the parallel G4 formed by dTGGGTTGGGTTGGGTTGGGT shows two quinoline subunits interacting with an external G-quartet through π-stacking, and solution nuclear magnetic resonance (NMR) confirms that the foldamer targets the 3' and 5' ends of this G4. 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 G4 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 G4 ligands, and their unique modular scaffold offers new avenues to further improve their affinity and selectivity.