The Impact of Halogenated Phenylalanine Derivatives on NFGAIL Amyloid Formation

Abstract

The hexapeptide hIAPP 22-27 (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 smallangle 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.

Gram-scale asymmetric synthesis of fluorinated amino acids using a chiral nickel(II) complex

“…1, a). 31,32 The hydrophobicity of fluorinated Abu and valine analogs has been discussed thoroughly in previous publications. 31 Fmoc-PfpGly ( 1.5 equiv.…”

Rational Design of Amphiphilic Fluorinated Peptides: Evaluation of Self-Assembly Properties and Hydrogel Formation

“…Such scaling behavior indicates a nearly circular cross-section for the fibrils of TfeGlyK16 (interpreted as circular cylinder) and a flat cross-section for DfeGlyK16 (interpreted as extended parallelepiped). 28,50 Data evaluation with both theoretical models in terms of time-resolved experiments [with measurement frames of n = 1 (recorded ca. 120 s after sample preparation) and n = 50 (recorded 3000 s after sample preparation)] revealed an increase of the major semi axis from a = 2.7 nm to 11.0 nm for DfeGlyK16 (1 wt%) and from 2.9 nm to 4.4 nm (2 wt%).…”

“…The replacement of a single C-H bond with C-F is generally considered to be isosteric. 20,21 To date, investigations of the effects of fluorinated amino acids on hydrophobicity 22,23 , secondary structure formation 24,25 , protein-protein interactions 26 , amyloid folding kinetics 27,28 , proteolytic stability 29 , chemical and biological properties of fluorinated peptide-based materials 30 , and on the integration of fluorine into living organisms 31,32 have been reported by our group. Vast majority of previous studies including our own efforts examining fluorinated amino acids in the context of peptide and protein chemistry were limited to the incorporation of one or only a few of these building blocks.…”

Peptide–Protein Interactions: From Drug Design to Supramolecular Biomaterials

“…A recent study on hydrophobic and π-π interactions in NFGAIL self-assembly based on fluorinated and iodinated phenylalanine analogues revealed a synergy between the aggregation behavior and hydrophobicity of the phenylalanine residue. These observations suggested an amyloidogenic behavior of NFGAIL independent from π-stacking geometries [ 157 ]. A systematic study on the molecular basis of Aβ-IAPP interaction resulted in the identification of short Aβ and IAPP peptide sequences as hot regions of the Aβ-IAPP hetero-cross-interaction interface.…”