A Modular Platform for Covalent, Photoswitchable Control over Enzyme Activity

doi:10.1055/s-0042-1751961

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“…The PTH peptides studied here are “more reversibly” fibrillating peptides, wherein the thermodynamic stabilization of the amyloid state is less and, therefore, also the kinetic barriers. , Nonetheless, until now, it has not been possible to control the reversibility of this process, as accomplished here via the introduction of a photoswitch. However, in contrast to other reversibly (photo)-switchable systems, such as reported for small molecule assemblies, adhesives, or photoswitchable enzymes, a full reversion of the aggregation of the current system is not reached, as expected, as the fibrillization and defibrillization processes depend on many factors, such as the kinetic barriers in either direction, the kind and number of nuclei present during the different switching cycles, or also the precipitation of fibrils.…”

Section: Resultsmentioning

confidence: 99%

Photocontrolled Reversible Amyloid Fibril Formation of Parathyroid Hormone-Derived Peptides

Paschold,

Schäffler,

Miao

et al. 2024

Bioconjugate Chem.

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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 PTH 25−37 , to control aggregation, revealing position-dependent effects. Through in silico design, synthesis, and experimental validation of 11 novel PTH 25−37 -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 PTH 25−37 , while in one of the AMPB-containing peptides, β-strands are antiparallel. Simulations further highlight the significance of π−π interactions in the latter. This multifaceted approach enabled the identification of a peptide that can undergo repeated phototriggered transitions between fibrillated and defibrillated states, as demonstrated by different spectroscopic techniques. With this strategy, we unlock the potential to manipulate PTH to reversibly switch between active and inactive aggregated states, representing the first observation of a photostimulus-responsive hormone.

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