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Despite significant advances in foldamer chemistry, tailored delivery systems based on foldamer architectures, which provide a high level of control over secondary structure, are curiously rare among non-viral technologies for transporting nucleic acids into cells. A potent pH-responsive, bioreducible cell-penetrating foldamer (CPF) was developed through covalent dimerization of a short (8-mer) amphipathic oligourea sequence bearing histidine-type units. This CPF exhibits a high capacity to assemble with pDNA and mediates efficient delivery of nucleic acids into the cell. Furthermore, it does not adversely affect cellular viability and was shown to compare favorably with a cognate peptide transfection agent based on His-rich sequences.

Foldaplex: A pH-responsive cell-penetrating foldamer (CPF) was designed for nucleic acid delivery. Histidine-type residues were introduced along the oligourea sequence to facilitate the release of the cargo into the cytoplasm. Dimerization of the urea-based foldamer sequence through a disulfide bridge enhanced cellular uptake and led to transfection efficiency comparable to that of commercially available transfection agents, as well as negligible cytotoxicity.

Nearly isosteric oxo to thioxo substitution was employed to interrogate the structure of foldamers with a urea backbone and explore the relationship between helical folding and hydrogen-bonding interactions. A series of oligomers with urea bonds substituted by thiourea bonds at discrete or all positions in the sequence have been prepared and their folding propensity was studied by using a combination of spectroscopic methods and X-ray diffraction. The outcome of oxo to thioxo replacements on the helical folding was found to depend on whether central or terminal ureas were modified. The canonical helix geometry was not affected upon insertion of thioureas close to the negative end of the helix dipole, whereas thioureas close to the positive pole were found to increase the terminal flexibility and cause helix fraying. Perturbation was amplified when a selenourea was incorporated instead, leading to a structure that is only partly folded.

Positional thiourea scan was used to examine the relationship between hydrogen-bonding interactions and helical folding in aliphatic N,N′-linked oligourea foldamers. The influence of the oxo to thioxo replacement was found to be minimal at the negative end of the helix dipole but more pronounced at positions, in which intramolecular CS⋅⋅⋅HN bonds can be formed. A partially unfolded state predominates when a selenourea linkage is introduced instead (see figure).