Composition and Conformation of Hetero- versus Homo-Fluorinated Triazolamers Influence their Activity on Islet Amyloid Polypeptide Aggregation.

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 ß-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.

5-Fluoro-1,2,3-triazole motif in peptides and its electronic properties.

The 5-fluoro triazole amino acid scaffold prepared by halogen exchange has been incorporated into peptides. From the X-ray diffraction of the 5-fluoro triazole motif, the main observation was an important localization on one side of the negative potential surface. The fluorine atom reveals a cylindrical shape in its deformation electron density.

Fluorinated Triazole Foldamers: Folded or Extended Conformational Preferences.

The Ministère de l'Enseignement Supérieur et de la Recherche (MESR) is thanked for financial support for José Laxio Arenas. The China Scholarship Council is thanked for financial support for Yaochun Xu. The authors thank Pr. Vadim Soloshonok and TOSOH F-TECH, Inc. for the kind gift of N-terbutyl-sulfinylimine.

Peptides and peptidomimetics as inhibitors of protein-protein interactions involving ß-sheet secondary structures.

Protein-protein interactions involving ß-sheet secondary structures have been questioned in many fatal human diseases such as cancer, autoimmune and neurodegenerative diseases. Small selective peptide derivatives and analogues are promising drug candidates for inhibiting this poorly known class of PPIs. In this review, we will highlight the main strategies developed for designing linear and cyclic peptide and peptidomimetic inhibitors of PPIs involving ß-sheet structures. These compounds either do not adopt preferred conformations or can mimic protein secondary structures such as ß-strands, ß-hairpins or α-helices.

Incorporating a Monofluoroalkene into the Backbones of Short Peptides: Evaluating the Impact on Local Hydrophobicity.

The local hydrophobicity of an amino acid residue in a peptide sequence can be determined by measuring the hydrophobicity index (φ0 ) by reversed-phase (RP) HPLC. Herein, the impact on the local hydrophobicity of the replacement of an amide by a monofluoroalkene unit in short peptides is discussed. Monofluoroalkene-containing dipeptides and tripeptides were synthesized, as well as their natural parent compounds, and the hydrophobicity indexes of these short peptides and peptidomimetics were determined. Comparison between the natural parent peptides and their alkene-containing analogues was made, and the dependence of the peptidomimetic analogues' behaviour on the pH and the solvent was studied. It was found that the presence of a monofluoroalkene unit enhanced a peptide's hydrophobicity.