Design and anti-inflammatory activity evaluation of tryptophan analogs as novel dipeptidyl peptidase I inhibitors.

Dipeptidyl peptidase I (DPP-I) mediates the processing and maturation of various serine proteases by cleaving dipeptide structures from N-terminus of zymogen proteins. This process enables DPP-I to participate in inflammatory cascades, thereby establishing it as a key therapeutic target for inflammatory diseases. Here, starting from a serendipitously discovered molecular block with weak DPP-I inhibitory activity, a series of tryptophan analogs were designed and synthesized. Following biological activity evaluation, compound C10b as a potent DPP-I inhibitor was identified. Through structure-activity relationship and docking analyses, the binding mode and key interactions were elucidated. In vitro results confirmed C10b could bind to and inhibit intracellular DPP-I activity, and further down-regulate the activity and expression levels of downstream neutrophil serine proteases, while exhibiting excellent anti-inflammatory activity and regulating the secretion of various inflammatory factors. In vivo results demonstrated C10b possessed acceptable toxicity and good pharmacodynamic activity. In the adjuvant-induced arthritis model in rats, C10b exerted an anti-inflammatory effect and reversed joint inflammation and tissue damage. Collectively, as a novel DPP-I inhibitor, C10b exhibits nice anti-inflammatory activity and considerable potential for further development, which supports its application in development of therapeutic agent for neutrophil-associated inflammatory diseases.