Exploring α-Glucosidase Inhibitory Peptides: Structure-Activity Relationship Analysis and Perspectives for Designing Potential Anti-Diabetic Agents

Context: 

α-Glucosidase (AG) inhibitory peptides represent a promising new class of therapeutic agents for the treatment of diabetes. However, there is a need to further understand the mechanisms and properties of these peptides.

Evidence Acquisition: 

In this comprehensive review, AG inhibitory peptides were categorized into three groups based on their length: short, medium, and long peptides. Data from the BioPEP-UWM database and recent publications were gathered to conduct a structure-activity relationship analysis for these peptides, focusing on identifying their reactive residues and AG binding sites.

 Through extensive examination, five substrate analogs (Trp376, Asp404, Ile441, Met519, and Phe649) and two catalytic residues (Asp518 and Asp616) were identified as the preferred inhibitory sites on AG. Furthermore, amino acid preferences and their positionings at different terminals on peptides, including the ultimate (N1 and C1), penultimate (N2 and C2), and antepenultimate (N3 and C3), were explored. Our findings revealed that these peptides were predominantly hydrophobic and tended to contain hydrophobic amino acids with hydrophobic alkyl/aryl side chains (such as lysine, glutamine, proline, and/or arginine). To gain further insights into peptide-AG interactions, docking analysis was performed, which highlighted the significance of hydrophobic bonds as the primary mode of interaction.

 By pooling all the findings, this review provided essential and practical information for the design and discovery of peptide-based anti-diabetic agents.