Modification of the Phenylalanine Residue and Its Effects on Peptide Hydrogelation

ABSTRACT Peptide‐based supramolecular hydrogels have emerged as a versatile class of biomaterials with promising applications in drug delivery, tissue engineering, and regenerative medicine. Among the various peptide‐based gels, phenylalanine‐containing short peptides have gained particular attention for their intrinsic ability to self‐assemble through π‐π stacking, hydrogen bonding, and hydrophobic interactions. In this paper, we have tuned the hydrogelation behavior of tripeptides containing a phenylalanine residue by modifying the length of the sidechain and the substituents on the phenyl ring. A parent tripeptide and its five different analogues containing modifications only of the phenylalanine residue were synthesized and all six peptides formed hydrogels. The structural organization and mechanical properties of the resulting hydrogels were examined using spectroscopic, rheological, and microscopic techniques. Distinct differences in gel strength and morphology were observed depending on the nature of the modification of the phenylalanine residue. The peptide containing a 4‐nitrophenylalanine residue produced the most mechanically robust gel, whereas the analogous peptides containing a 4‐methoxyphenylalanine and a bishomo‐phenylalanine formed the weakest gel network. Understanding these structure–property relationships provides critical insights for the rational design of functional peptide‐based materials and underscores the need for systematic exploration of chemical modifications in supramolecular hydrogel systems.