| Autor: |
Daniel C. Okoye, Adeline M. Fanni, M. Lisa Phipps, Jennifer S. Martinez, Florencia A. Monge, Julia J. Hammond, Eva Y. Chi, Gabriella Brinkley, Tye D. Martin, David G. Whitten, Fahimeh Maghsoodi, Deborah G. Evans |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.1101/2021.11.03.467121 |
| Popis: |
Photodynamic therapy (PDT) has been explored as a therapeutic strategy to clear toxic amyloid aggregates involved in neurodegenerative disorders such as Alzheimer’s disease. A major limitation of PDT is off-target oxidation, which can be lethal for the surrounding cells. We have shown that a novel class of oligo-p-phenylene ethynylene-based compounds (OPEs) exhibit selective binding and fluorescence turn-on in the presence of pre-fibrillar and fibrillar aggregates of disease-relevant proteins such as amyloid-β (Aβ) and α-synuclein. Concomitant with fluorescence turn-on, OPE also photosensitizes singlet oxygen under illumination through the generation of a triplet state, pointing to the potential application of OPEs as photosensitizers in PDT. Herein, we investigated the photosensitizing activity of an anionic OPE for the photo-oxidation of toxic Aβ aggregates and compared its efficacy to the well-known but non-selective photosensitizer methylene blue (MB). Our results show that while MB photo-oxidized both monomeric and fibrillar conformers of Aβ40, OPE oxidized only Aβ40 fibrils, targeting two histidine residues on the fibril surface and a methionine residue located in the fibril core. Oxidized fibrils were shorter and more dispersed, but retained the characteristic β-sheet rich fibrillar structure and the ability to seed further fibril growth. Importantly, the oxidized fibrils displayed low toxicity. We have thus discovered a class of novel theranostics for the simultaneous detection and oxidization of amyloid aggregates. Importantly, the selectivity of OPE’s photosensitizing activity overcomes the limitation of off-target oxidation of currently available photosensitizers, and represents a significant advancement of PDT as a viable strategy to treat neurodegenerative disorders. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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