Abstract
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 pi-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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Minor revisions on the NMR section. Figure 8 was updated. PDB validation report is added to the supporting information.
