Can the stereogenicity in aromatic/non-aromatic residues influence the mechanical integrity, antimicrobial and anti-inflammatory preferences of auxin derivatized hydrogels?

Abstract

A heterochiral diphenylalanine auxin derivative has exhibited remarkable mechanical strength and antimicrobial propensities at room temperature (N. Khan, A. Gupta, V. Shivhare, R. Ahuja, M. Varshney, A. Basu, and A. Dutt Konar New J. Chem., 2022, Just Accepted) (hydrogelators I–II). To explore the impact of stereogenicity on the aromatic/non-aromatic amino acid residues on these dimensions, herein we report the design and development of hydrogelators III–V, with varied chiral centers, that immobilized physiological buffer at room temperature, in a fashion akin to that of hydrogelators I–II. Interestingly, our rheological experiments demonstrated that the mechanical integrity of the heterochiral hydrogelator III, containing hydrophobic amino acid Leu, as a replacement residue in diphenylalanines, is much higher in comparison to that of the homochiral diphenylalanine analogs (hydrogelators IV–V). To reinforce this observation, we performed density functional theory (DFT) calculations with the hydrogelators. Our investigations illustrated that the cause of such high mechanical integrity might be due to the antiparallel orientation of naphthyl units and the Leu(1) sidechain of hydrogelator III, unlike other homochiral hydrogelators IV–V, where the phenylalanine(1)/naphthyl rings are perpendicularly organized. Overall, studies indicate that the inclusion of appropriate chiral residue at a relevant position in the sequence enlightens a rational strategy towards regulating the mechanical strength of the hydrogels, optimized for need-based applications. The conformational and morphological analysis suggested the presence of β-sheet-like structures stabilized by intermolecular hydrogen bonding. Surprisingly hydrogelator III was found to be selective towards Gram-positive microorganisms, namely Staphylococcus aureus and S. mutans, and inactive against Gram-negative Escherichia coli and Klebsiella pneumoniae. However, the homochiral derivatives showed no particular preference for exhibiting antibacterial action. Also, the anti-fungal behavior towards C. albicans and A. niger and the anti-inflammatory response in matrix metalloproteinase receptors were found to be significantly affected by chirality. Thus, our efforts focus on how chirality in the peptide sequence has a profound impact on gelation strength, potency, and selectivity. Indeed, this work establishes innovative design principles for the development of efficient therapeutics with the ability to address the challenges arising due to microbial infections as well as inflammations collectively in one shot.