Biocompatible and biostable supramolecular hydrogels from folded peptidomimetics.

Abstract

Peptidomimetics have emerged as indispensable tools in medicinal chemistry, renowned for their therapeutic uses and ability to mimic protein secondary structures. Despite their biological and structural relevance, their use in the design of higher order supramolecular structures has remained largely unexplored. Herein, we report supramolecular hydrogelation from a minimalist-designed peptidomimetic composed of a non-canonical β-hydroxy-γ-amino acid (statine) and canonical phenylalanine (Phe). The resultant hydrogel comprises entangled fibers, exhibits viscoelastic and thixotropic properties, is thermo- and mechano-sensitive as well as injectable. Furthermore, upon mutating the peptidomimetic sequence by swapping the C-terminal aromatic phenylalanine with a more hydrophilic serine residue, the modified peptidomimetic forms a more hydrated hydrogel matrix, which more efficiently supports the viability and proliferation of L929 fibroblast cells than the initial hybrid peptide. Notably, due to the presence of a non-canonical backbone, both the hydrogelators are proteolytically stable. Combined biophysical analyses, density functional theory (DFT) calculations and 2D NMR spectroscopy reveal that the hydrogel-forming peptidomimetic adopts a C9 helical conformation, which distinguishes it from the conformations typically observed in most Fmoc-terminated peptide hydrogelators. The present study highlights the importance of unusual statine residues in the development of minimal peptidomimetic hydrogelators and expanding the secondary structural diversity for the rational design of short peptidomimetic hydrogelators.