Multivalent MMP-12 inhibitors as a valuable approach to counteract the intestinal epithelial barrier impairment and inflammation in an in vitro model mimicking intestinal high-fat exposure

Intestinal epithelial barrier (IEB) impairment represents a prodromal event underlying obesity and related systemic inflammation. In this context, metalloproteinase-12 (MMP-12) has been reported to increase the IEB permeability through the reduction of tight junction proteins expression. Herein we report our effort to develop a small series of MMP-12 inhibitors as potential agents able to counteract the IEB alterations and intestinal inflammation associated with obesity. Three multivalent and gut-restricted carboxylate-based selective inhibitors of MMP-12 were synthesized and tested first on human recombinant MMP-12 isolated enzyme and then on human intestinal epithelial Caco-2 cells treated with palmitate (PA) and lipopolysaccharide (LPS), to mimic the in vivo exposure to hypercaloric diet. Trimeric derivative 2 in particular showed a nanomolar activity against MMP-12 and was able to increase both ZO-1 and claudin-1 tight junction expression in a concentration-dependent manner, already at a concentration of 50 nM. This compound was also the most effective in reducing interleukin-1β release from Caco-2 cells treated with PA and LPS. This preliminary work indicates that a pharmacological modulation of MMP-12 represents a promising strategy to counteract the impairment of IEB integrity and intestinal inflammation associated with obesity.