Chem. Eur. J. 26, 14612-14622, https://doi.org/10.1002/chem.202001716
J. Kaffy J., Berardet C., Mathieu L., Legrand B., Taverna M., Halgand F., Van Der Rest G., Maillard L. T., Ongeri S.
Abstract
Type 2 diabetes (T2D) and Alzheimer’s disease (AD) belong to the 10 deadliest diseases and are sorely lacking in effective treatments. Both pathologies are part of the degenerative disorders named amyloidoses, which involve the misfolding and the aggregation of amyloid peptides, hIAPP for T2D and Aβ1‐42 for AD. While hIAPP and Aβ1‐42 inhibitors have been essentially designed to target β‐sheet‐rich structures composing the toxic amyloid oligomers and fibrils of these peptides, the strategy aiming at trapping the non‐toxic monomers in their helical native conformation has been rarely explored. We report herein the first example of helical foldamers as dual inhibitors of hIAPP and Aβ1‐42 aggregation and able to preserve the monomeric species of both amyloid peptides. A foldamer composed of 4‐amino(methyl)‐1,3‐thiazole‐5‐carboxylic acid (ATC) units, adopting a 9‐helix structure reminiscent of 310 helix, was remarkable as demonstrated by biophysical assays combining thioflavin‐T fluorescence, transmission electronic microscopy, capillary electrophoresis and mass spectrometry.
