RESUMO
Deciphering the most promising strategy for the evolution of potential wound-healing therapeutics is one of the greatest challenging affairs to date. The development of peptide-based smart scaffolds with innate antimicrobial, anti-inflammatory, and antioxidant properties is an appealing way out. Aligned to the goal a set of Hydrogelators I-IV were developed utilizing the concept of chiral orchestration in diphenylalanine fragment, such that the most potent construct with all the bench marks namely mechanoresponsiveness, biocompatibility, consistent antimicrobial and antioxidant properties, could be fished out from the design. Interestingly, our inâ vitro Antifungal and Lipid peroxidation analysis identified the homochiral isomer Boc-δ-Ava-L-Phe-L-Phe-OH (Hydrogelator I), as an ideal candidate for the wound healing experiment, so we proceeded for the inâ vivo histopathological and antioxidant measurements in Wister rats. Indeed the wound images obtained from the different sets of animals on the 14th day of treatment demonstrated that with increased recovery time, hydrogelator I displayed a significant reduction in the lesion diameter compared to the marketed drug, and negative control. Even the histopathological measurements using H & E staining demonstrated diminished tissue destruction, neutrophil infiltration necrosis, and lymphatic proliferation in the hydrogelators, in comparison to others, backed by inâ vivo lipid peroxidation data. Overall our investigation certifies hydrogelator I as an effective therapeutic for managing the wound healing complication.
RESUMO
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 ß-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.