Chiral Orchestration: A Tool for Fishing Out Tripeptide-Based Mechanoresponsive Supergelators Possessing Anti-Inflammatory and Antimicrobial Properties

Deciphering the most promising strategy for the evolution of microbial infection and inflammation-based therapeutics is one of the most challenging affairs to date. Development of peptide-based smart supergelators with innate antimicrobial and anti-inflammatory activities is an appealing way out. In this work, the hydrogelators Boc-δ-Ava-(X)-Phe-(Y)-Phe-OH (I: X = Y = L; II: X = L; Y = D; III: X = D; Y = L; IV: X = Y = D, Ava: δ-amino valeric acid) have been designed and fabricated by strategic chiral tuning to investigate the effect of alternation of configuration(s) of Phe residues in governing the fashion of self-aggregation and macroscopic properties of peptides. Interestingly, all of the molecules formed mechanoresponsive hydrogels under physiological conditions with a nanofibrillar network. The spectroscopic experiments confirmed the conformation of the hydrogelators to be supramolecular β-sheets formed through the self-association of S-shaped constructs stabilized by noncovalent interactions. Indeed, the present work demonstrates a rational approach toward regulating the mechanical integrity of the hydrogels through systematic inclusion of d-amino acids at appropriate positions in the sequence. The hydrogelators were found to possess antimicrobial activity against both Gram-positive bacteria (Staphylococcus aureus and Streptococcus mutans) and Gram-negative bacteria (Escherichia coli and Klebsiella pneumonia) while retaining their biocompatibility toward mammalian cells (as revealed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), hemolysis, and lipid peroxidation assays). These scaffolds also exhibited anti-inflammatory activities, as observed through in vitro MMP2/MMP9 inhibition studies and in vivo animal models, namely, the rat pouch model for acute inflammation. We anticipate that the discovery of these intelligent materials with multifunctional capabilities holds future promise as preferential therapeutics for the treatment of bacterial infections as well as associated inflammations arising alone or as side effects of biomaterial implants.