α-Glucosidase and PTP-1B Inhibitors from Malbranchea dendritica

Area of Science:

• Natural Product Chemistry
• Enzymology
• Pharmacology

Background:

• Fungal extracts are a source of bioactive compounds.
• Alpha-glucosidase inhibitors and Protein Tyrosine Phosphatase 1B (PTP-1B) inhibitors are targets for metabolic disease treatment.

Purpose of the Study:

• To isolate and characterize compounds from Malbranchea dendritica with alpha-glucosidase and PTP-1B inhibitory activities.
• To evaluate the in vitro and in vivo efficacy of isolated compounds.

Main Methods:

• Fractionation of fungal extract, compound isolation, and structural elucidation (NMR, MS).
• Enzyme inhibition assays (alpha-glucosidase, PTP-1B) and kinetic analysis.
• In vivo sucrose tolerance test in mice, compound reduction, and computational docking studies.

Main Results:

• Gymnoascolide A (1) demonstrated potent yeast alpha-glucosidase inhibition (IC50 = 0.556 mM) and reduced postprandial glucose levels in mice.
• Enantiomers 1a and 1b, derived from gymnoascolide A, retained alpha-glucosidase inhibitory activity and showed potential for improved drug-likeness.
• Xanthone sydowinin B (3) moderately inhibited PTP-1B (IC50 = 0.081 mM).
• Docking studies suggested allosteric binding of compounds 1, 1a, and 1b to alpha-glucosidase and compound 3 to PTP-1B.

Conclusions:

• Gymnoascolide A is a promising lead compound for alpha-glucosidase inhibition with potential therapeutic applications.
• Enantiomeric modification of gymnoascolide A may enhance its drug-like properties.
• Malbranchea dendritica is a source of diverse bioactive natural products, including xanthones with PTP-1B inhibitory activity.