Betaine-Conjugated ß-Peptide Foldamers: Influence of Quaternary Charge on Self-Organization and MorphologyFormation

The modification of well-known β-peptide helices has been achieved by the application of N-terminal betaine conjugation. The 3D self-organization of oligomers formed by [1S,2S]-2-aminocyclopentanecarboxylic acid (ACPC), [1R,2R]-2-aminocyclohexanecarboxylic acid (ACHC), and an alternating heterochiral homooligomer of [1S,2S]-ACPC and [1R,2R]-ACPC was studied. Results of NMR, ECD, FT-IR, and molecular modeling showed that for [1S,2S]-ACPC pentamer (1), the betaine conjugation did not affect the folding to an H12 helix. In contrast, for the [1R,2R]-ACHC tetramer (2) betaine conjugation notably influenced the folding, and an H14 helix was observed instead of the expected H10 helix. In addition, this is the first observation of self-association for an H12 helix forming β-peptide. Based on TEM images, this association leads to vesicle morphologies. For the alternating heterochiral homooligomer [1S,2S]-ACPC and the [1R,2R]-ACPC pentamer (3), betaine conjugation enhances the solubility of the system. Moreover, the formation of an expected E-strand can be anticipated, since self-association was found in the form of a fibrin net-like structure in TEM images. Betaine conjugates described herein open a new area of bioactive peptide foldamer construction, since the introduced quaternary charges may lead to important receptor-ligand interactions, while potential material science applications can also be realized.