Excited-State Intramolecular Hydrogen Transfer of Compact Molecules Controls Amyloid Aggregation Profiles.

Abstract

Developing chemical methodologies to directly modify harmful biomolecules affords the mitigation of their toxicity by persistent changes in their properties and structures. Here we report compact photosensitizers composed of the anthraquinone (AQ) backbone that undergo excited-state intramolecular hydrogen transfer, effectively oxidize amyloidogenic peptides, and, subsequently, alter their aggregation pathways. Density functional theory calculations showed that the appropriate position of the hydroxyl groups in the AQ backbone and the consequent intramolecular hydrogen transfer can facilitate the energy transfer to triplet oxygen. Biochemical and biophysical investigations confirmed that these photoactive chemical reagents can oxidatively vary both metal-free amyloid-β (Aβ) and metal-bound Aβ, thereby redirecting their on-pathway aggregation into off-pathway as well as disassembling their preformed aggregates. Moreover, the in vivo histochemical analysis of Aβ species produced upon photoactivation of the most promising candidate demonstrated that they do not aggregate into oligomeric or fibrillar aggregates in the brain. Overall, our combined computational and experimental studies validate a light-based approach for designing small molecules, with minimum structural complexity, as chemical reagents targeting and controlling amyloidogenic peptides associated with neurodegenerative disorders.