Aromatic Foldamer Mimics of B-DNA: Targeting the Alpha-Helix

Protein-nucleic acid interactions (PNIs) play a central role in biology and their control would enable long-desired biological interventions and future therapeutic applications. However, synthetic molecules that reproduce the overall shape and surface features of nucleic acids to interfere with PNIs have been lacking because, up to now, it has not been possible to design such extended and complex abiotic interactions interfaces. Due to their distinct chemical composition, predictable shapes, large size and conformational stability, aromatic oligoamide foldamers (AOFs) are prime candidates for breaking new ground in this field. FOLOF aims to develop AOF-based surface mimics of the B-DNA double helix targeted to the large ensemble of sequence-selective PNIs mediated by alpha-helices.Based on the PIs expertise in AOF science, FOLOF will proceed by 1) expanding the chemistry tool box to enable specific design objectives; 2) optimizing the automation of AOF synthesis for the fast delivery of long sequences; 3) identifying structural features of protein-foldamer complexes and specific foldamer features that make them outcompete DNA binding; 4) establishing protocols to iteratively improve protein binding affinity and selectivity for AOFs, and AOF-DNA covalent hybrids; and 5) developing computational tools for ab initio AOF-based DNA mimic design. Through a strategic combination of chemical synthesis, computational predictions, crystallographic structural analysis, binding studies, and screening tools, FOLOF will push the production of abiotic molecular mimics of nucleic acids to a completely new ensemble.