Macroalgal Peptides with Predicted α-Glucosidase Inhibitory Activity: Preparation and Molecular Docking

TL;DR

This study identifies peptides from a red alga that can inhibit an enzyme linked to blood sugar control, with potential for developing new treatments for diabetes.

Contribution

The study introduces novel low-molecular-weight peptides from Palmaria palmata with strong α-glucosidase inhibition and provides structural insights for drug design.

Findings

Alcalase®-derived peptides showed highest α-glucosidase inhibition with an IC50 of 2.48 mg·mL−1.

Peptides RADIPFRRA and DGIAEAWLG bind to the enzyme's active site, while FWSQIFGVAF binds to a peripheral site.

Low-molecular-weight peptides (<1 kDa) exhibited the strongest inhibitory activity.

Abstract

This study investigated the α-glucosidase inhibitory potential of enzymatic/alkaline treatments from Palmaria palmata using different proteases and pairwise combinations thereof. Treatments prepared with Alcalase®, Flavourzyme®, and Formea® Prime, alone or in combination, were evaluated for dose-dependent inhibitory activity. Alcalase®-derived treatments exhibited the highest α-glucosidase inhibition, achieving an IC50 of 2.48 mg·mL−1, outperforming other treatments and combinations. Membrane fractionation of the Alcalase®-derived treatment into >5 kDa, 3–5 kDa, 1–3 kDa, and <1 kDa fractions revealed a size-dependent trend, with the <1 kDa fraction showing the strongest inhibition (IC50 of 1.94 mg·mL−1). Three peptides, RADIPFRRA, DGIAEAWLG, and FWSQIFGVAF, from the <1 kDa fraction were identified as potential α-glucosidase inhibitors using the BIOPEP-UWM database and were further selected based on a Peptide Ranker score above 0.6 for in silico docking analyses. Docking revealed distinct binding modes: RADIPFRRA and DGIAEAWLG occupied the catalytic cleft, interacting with key residues (Asp518, Asp616, Trp481, Trp613) consistent with competitive inhibition, whereas FWSQIFGVAF bound to a peripheral site, suggesting potential allosteric modulation. Physicochemical analysis further highlighted differences in charge and isoelectric point correlating with their binding behavior. Together, these findings demonstrate that low-molecular-weight peptides derived from P. palmata proteins, particularly those generated by Alcalase®, possess significant α-glucosidase inhibitory activity, and provide structural insights for the rational design of peptide-based modulators of carbohydrate metabolism.

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