Paschold, A. et. al. Bioconjugate Chemistry, 2024, 35, 7, 981–995, https://doi.org/10.1021/acs.bioconjchem.4c00188
Peptide fibrillization is crucial in biological processes such as amyloid-related diseases and hormone storage, involving complex transitions between folded, unfolded, and aggregated states. We here employ light to induce reversible transitions between aggregated and nonaggregated states of a peptide, linked to the parathyroid hormone (PTH). The artificial light-switch 3-{[(4-aminomethyl)phenyl]diazenyl}benzoic acid (AMPB) is embedded into a segment of PTH, the peptide PTH25–37, to control aggregation, revealing position-dependent effects. Through in silico design, synthesis, and experimental validation of 11 novel PTH25–37-derived peptides, we predict and confirm the amyloid-forming capabilities of the AMPB-containing peptides. Quantum-chemical studies shed light on the photoswitching mechanism. Solid-state NMR studies suggest that β-strands are aligned parallel in fibrils of PTH25–37, while in one of the AMPB-containing peptides, β-strands are antiparallel. Simulations further highlight the significance of π–π interactions in the latter. Copyright © 2024 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0