Rational Sequence Modification Upgrades a Food-Derived Peptide into a Stronger Dual-Functional Regulator of α-Glucosidase Activity and Insulin Resistance

Inhibition of α-glucosidase and improvement of insulin resistance (IR) are key strategies for treating type 2 diabetes mellitus (T2DM). Our previous work obtained a novel α-glucosidase inhibitory peptide, FAPSW. However, its activity was weaker than acarbose. To further enhance its activities, 17 novel peptides were constructed by amino acid substitution using FAPSW as a template. Among them, YAPSW (IC50 = 0.126 ± 0.008 mM) exhibited stronger α-glucosidase inhibition than FAPSW and acarbose. Molecular docking suggested that hydrogen bonds were not the sole determinants of peptide-mediated α-glucosidase inhibition, while molecular dynamics simulations revealed that the enhanced inhibitory activity of YAPSW primarily resulted from its more stable binding to 3A4A. Moreover, FAPSW and YAPSW could improve IR and YAPSW exhibited stronger effects on IRS-1/PI3K/AKT signaling pathway than FAPSW. This study provides insights into optimizing α-glucosidase inhibitory peptides and supports the potential application of YAPSW as a multifunctional food ingredient for T2DM management.