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Updated: Jun 14, 2025
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Rapid Generation of Amyloid from Native Proteins In vitro
Published on: December 5, 2013
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Converting the Amyloidogenic Islet Amyloid Polypeptide into a Potent Nonaggregating Peptide Ligand by Side
Margaryta Babych1,2, Michael L Garelja3, Phuong Trang Nguyen1,2
1Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montréal H3C 3P8, Canada.
Journal of the American Chemical Society
|September 3, 2024
Summary
Macrocyclization stabilizes islet amyloid polypeptide (IAPP) into an alpha-helix, preventing toxic aggregation while preserving receptor activity. This strategy offers a promising therapeutic approach for type 2 diabetes.
Area of Science:
- Biochemistry
- Molecular Biology
- Endocrinology
Background:
- Islet amyloid polypeptide (IAPP), or amylin, is crucial for physiological roles but linked to type 2 diabetes via aggregation in pancreatic islets.
- IAPP's conformational flexibility, from random coil to alpha-helix, dictates its function, receptor activation, and amyloid formation.
- The interplay between IAPP's helical folding, aggregation, and receptor activity is complex and challenging to study.
Purpose of the Study:
- To investigate the impact of helical folding on IAPP's function-toxicity balance.
- To explore macrocyclization as a method to control IAPP conformation and mitigate toxicity.
- To assess the receptor activity of conformationally restricted IAPP analogs.
Main Methods:
- Utilizing side chain-to-side chain stapling via azide-alkyne cycloaddition to create intramolecularly macrocyclized IAPP.
- Employing (i; i+4) macrocyclization to specifically stabilize IAPP in an alpha-helical conformation.
- Evaluating the effects of macrocyclization on IAPP's lipid perturbation, membrane interaction, cytotoxicity, and receptor binding.
Main Results:
- Macrocyclization successfully constrained IAPP into a stable alpha-helical structure, significantly inhibiting amyloid fibril formation.
- Helical IAPP derivatives demonstrated reduced ability to perturb lipid bilayers and cell membranes, leading to decreased cytotoxicity.
- The stabilized alpha-helical IAPP analogs retained moderate to high potency for their cognate G protein-coupled receptors.
Conclusions:
- Macrocyclization is an effective strategy to prevent amyloidogenic peptide hormone aggregation and associated toxicity.
- Stabilizing IAPP in an alpha-helical conformation preserves essential receptor activity while eliminating harmful aggregation.
- This approach holds promise for developing therapeutics targeting IAPP-related disorders, such as type 2 diabetes.
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