Molecular Engineering of Minimalistic Amphiphilic Peptidomimetics for the Design of Biocompatible Hydrogels with Potential Antibacterial Activity

Abstract

Peptidomimetics have long been of interest in drug discovery; however, their use in the design of higher-order supramolecular structures is limited. Herein, we report the higher-order supramolecular self-assembly of rationally designed ultrashort cationic peptidomimetics by harnessing the unique conformational preferences and enhanced molecular interactions of homologated noncanonical γ- and β-hydroxy-γ-amino acid residues. The intrinsic amphiphilic character of these peptidomimetics drives their self-assembly into fibrillar, viscoelastic, injectable hydrogels with distinctive conformational and supramolecular organization. Furthermore, systematic structural engineering of peptidomimetics yielded a hydrogel matrix with a more hydrated microenvironment conducive for the culture of L929 fibroblast cells. Moreover, the cationic fibrillar networks exhibited potent antibacterial activity, highlighting their potential as biocompatible antimicrobial biomaterials. This study demonstrates the importance of rational structural engineering of ultrashort peptidomimetics for the generation of functional biomaterials.