Relation between conformation and activity on islet amyloid polypeptide aggregation of fluorinated foldamers based on N-difluoromethyl-1,4-triazole amino acids

• Published in: Chemistry : a European journal p. e202303887
• Main Authors: Laxio Arenas, José, Lesma, Jacopo, Ha-Duong, Tap, Sahoo, Bikash Ranjan, Ramamoorthy, Ayyalusamy, Tonali, Nicolo, Soulier, Jean-Louis, Halgand, Frederic, Giraud, François, Crousse, Benoit, Kaffy, Julia, Ongeri, Sandrine
• Format: Journal Article
• Language: English
• Published: Germany 13.03.2024
• Subjects: Triazole; Fluorine; Amyloid; peptidomimetic; foldamer
• ISSN: 1521-3765

Novel fluorinated foldamers based on aminomethyl-1,4-triazolyl-difluoroacetic acid (1,4-Tz-CF2) units were synthesized and their conformational behaviour was studied by NMR and molecular dynamics. Their activity on the aggregation of the human islet amyloid polypeptide (hIAPP) amyloid protein was evaluated by fluorescence spectroscopy and mass spectrometry. The fluorine labelling of these foldamers allowed the analysis of their interaction with the target protein. We demonstrated that the preferred extended conformation of homotriazolamers of 1,4-Tz-CF2 unit increases the aggregation of hIAPP, while the hairpin-like conformation of more flexible heterotriazolamers containing two 1,4-Tz-CF2 units mixed with natural amino acids from the hIAPP sequence reduces it, and more efficiently than the parent natural peptide. The longer heterotriazolamers having three 1,4-Tz-CF2 units adopting more folded hairpin-like and ladder-like structures similar to short multi-stranded β-sheets have no effect. This work demonstrates that a good balance between the structuring and flexibility of these foldamers is necessary to allow efficient interaction with the target protein..