Novel Dipeptidyl Peptidase IV Inhibitory Peptides Derived from Sesame Proteins: Screening, Mechanisms and Anti-Hyperglycemic Effects in Zebrafish Larvae

The growing global concern regarding diabetes, particularly type 2 diabetes (T2D), calls for innovative approaches to disease management. Inhibition of dipeptidyl peptidase-IV (DPP-IV) has emerged as a promising strategy for T2D treatment. Food-derived peptides from various sources have shown potential in inhibiting DPPIV activity. Sesame, a significant crop rich in nutrients, holds untapped potential in this regard. In this study, we used in silico tools to identify and screen two novel DPP-IV inhibitory tripeptides (WPR and MPR) from sesame proteins. Both tripeptides displayed robust inhibitory activity in vitro, with WPR exhibiting non-competitive inhibition (IC50 of 85.85 +/- 2.54 mu M) and MPR showing competitive inhibition (IC50 of 160.17 +/- 5.46 mu M). Significantly, WPR demonstrated strong stability across a range of temperature and pH conditions compared to MPR. Molecular docking analysis revealed that WPR formed three hydrogen bonds with DPP-IV at Asp545, Val546, and Gly741, while MPR established five hydrogen bonds at His740, Ser630, and Tyr547. Molecular dynamics simulations analysis indicated that WPR and MPR bind stably to DPP-IV. In vivo experiments using zebrafish larvae showed the effectiveness of both WPR and MPR in reducing glucose levels, coupled with their regulatory influence on glucagon and insulin genes expression. These findings emphasize the potential of sesamederived tripeptides as a novel and secure source of DPP-IV inhibitors.