121341-41-1Relevant academic research and scientific papers
The Impact of Halogenated Phenylalanine Derivatives on NFGAIL Amyloid Formation
Chowdhary, Suvrat,Moschner, Johann,Mikolajczak, Dorian J.,Becker, Maximilian,Thünemann, Andreas F.,K?stner, Claudia,Klemczak, Damian,Stegemann, Anne-Katrin,B?ttcher, Christoph,Metrangolo, Pierangelo,Netz, Roland R.,Koksch, Beate
, p. 3544 - 3554 (2020/10/02)
The hexapeptide hIAPP22–27 (NFGAIL) is known as a crucial amyloid core sequence of the human islet amyloid polypeptide (hIAPP) whose aggregates can be used to better understand the wild-type hIAPP′s toxicity to β-cell death. In amyloid research, the role of hydrophobic and aromatic-aromatic interactions as potential driving forces during the aggregation process is controversially discussed not only in case of NFGAIL, but also for amyloidogenic peptides in general. We have used halogenation of the aromatic residue as a strategy to modulate hydrophobic and aromatic-aromatic interactions and prepared a library of NFGAIL variants containing fluorinated and iodinated phenylalanine analogues. We used thioflavin T staining, transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) to study the impact of side-chain halogenation on NFGAIL amyloid formation kinetics. Our data revealed a synergy between aggregation behavior and hydrophobicity of the phenylalanine residue. This study introduces systematic fluorination as a toolbox to further investigate the nature of the amyloid self-assembly process.
Modulation of fibrillation of hIAPP core fragments by chemical modification of the peptide backbone
Andreasen, Maria,Nielsen, S?ren B.,Mittag, Tina,Bjerring, Morten,Nielsen, Jakob T.,Zhang, Shuai,Nielsen, Erik H.,Jeppesen, Martin,Christiansen, Gunna,Besenbacher, Flemming,Dong, Mingdong,Nielsen, Niels Chr.,Skrydstrup, Troels,Otzen, Daniel E.
experimental part, p. 274 - 285 (2012/05/20)
The well-ordered cross β-strand structure found in amyloid aggregates is stabilized by many different side chain interactions, including hydrophobic interactions, electrostatic charge and the intrinsic propensity to form β-sheet structures. In addition to the side chains, backbone interactions are important because of the regular hydrogen-bonding pattern. β-Sheet breaking peptide analogs, such as those formed by N-methylation, interfere with the repetitive hydrogen bonding pattern of peptide strands. Here we test backbone contributions to fibril stability using analogs of the 6-10 residue fibril core of human islet amyloid polypeptide, a 37 amino acid peptide involved in the pathogenesis of type II diabetes. The Phe-Gly peptide bond has been replaced by a hydroxyethylene or a ketomethylene group and the nitrogen-atom has been methylated. In addition, we have prepared peptoids where the side chain is transferred to the nitrogen atom. The backbone turns out to be extremely sensitive to substitution, since only the minimally perturbed ketomethylene analog (where only one of the - NH - groups has been replaced by - CH 2-) can elongate wildtype fibrils but cannot fibrillate on its own. The resulting fibrils displayed differences in both secondary structure and overall morphology. No analog could inhibit the fibrillation of the parent peptide, suggesting an inability to bind to existing fibril surfaces. In contrast, side chain mutations that left the backbone intact but increased backbone flexibility or removed stabilizing side-chain interactions had very small effect on fibrillation kinetics. We conclude that fibrillation is very sensitive to even small modifications of the peptide backbone.
Anti-fibril peptides
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Page/Page column 9, (2008/06/13)
Short peptides containing Cα,α-dipropylglycine (Dpg) at alternating sequence positions were synthesized and examined for conformational behavior. Peptide assembly was performed using Fmoc-solid-phase chemistry where the coupling with PyAOP could be significantly enhanced at elevated temperature. Circular dichroism (CD) and NMR conformational studies revealed that incorporation of Dpg residues induced folded structures into peptides. It was observed that Dpg residues adopted helical conformation in a helix-promoting sequence. The resulting helical structure was comprised of consecutive β-turns whose structure was stabilized by salt bridge in aqueous solution. In this study, the preparation of sterically and polyfunctional Cα,α-disubstituted amino acids (ααAAs) via alkylation of ethyl nitroacetate and transformation into derivatives ready for incorporation into peptides are described. Treatment of ethyl nitroacetate with N,N-diisopropylethylamine in the presence of a catalytic amount of tetraalkylammonium salt, followed by the addition of an activated alkyl halide or Michael acceptor, gave the doubly C-alkylated product in good to excellent yields. Selective nitro reduction with Zn in acetic or hydrogen over Raney Ni gave the corresponding amino ester that, upon saponification, can be protected with the fluorenylmethyloxycarbonyl (Fmoc) group. The synthesis of a sterically demanding Cα,α-dibenzylglycine (Dbzg), and an orthogonally protected, tetrafunctional Cα,α-disubstituted analogue of aspartic acid Bcmg is described. The preparation of amyloid fibril blocker peptides based on amyloid peptide hydrophobic core Aβ16-20 is described. These blocker peptides containing sterically
