A mechanoresponsive heterochiral hydrogelator as a potential matrix metalloproteinase-2 inhibitor: unravelling its anti-inflammatory efficacy in vitro and in vivo†

Inflammations are innate and adaptive immune responses that get instigated in reciprocation to infection. However, if left unchecked, they pose a formidable challenge in clinical settings. In search of user-friendly solutions, our work delineated a rational combinatorial strategy, harnessing chiral orchestration in a triphenylalanine fragment and appending it to δ-amino valeric acid at the N-terminus (hydrogelators I–VIII) such that a potential matrix metalloproteinase-2 (MMP2) inhibitor could be fished out from the design. Our rigorous investigations revealed that from a pool of eight constructs, hydrogelator VIII, with a DLL configuration at the triphenylalanines, displayed excellent MMP2 inhibitory activities in vitro, which was further supported by molecular modelling studies. Besides, the β-sheet structured scaffold not only showed substantial antibacterial efficacy against the Gram-positive pathogens S. aureus, S. mutans, B. subtilis and E. fecalis but also exhibited proteolytic stability and biocompatibility towards mammalian cells. Furthermore, the scaffold possessed high mechanical strength at physiological pH and mechanical stress-triggered gel–sol–gel transition properties. Finally, the in vivo efficacy was evaluated using an air pouch model of acute inflammation in albino mice that certified hydrogelator VIII as a promising anti-inflammatory therapeutic to pave the path for future healthcare management.