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

Content Provider	Europe PMC
Author	Hong, Mannkyu Kim, Mingeun Yoon, Jiwon Lee, Seung-Hee Baik, Mu-Hyun Lim, Mi Hee
Copyright Year	2022
Abstract	Developing chemical methodologies to directly modifyharmful biomoleculesaffords the mitigation of their toxicity by persistent changes intheir properties and structures. Here we report compact photosensitizerscomposed of the anthraquinone (AQ) backbone that undergoexcited-state intramolecular hydrogen transfer, effectively oxidizeamyloidogenic peptides, and, subsequently, alter their aggregationpathways. Density functional theory calculations showed that the appropriateposition of the hydroxyl groups in the AQ backbone andthe consequent intramolecular hydrogen transfer can facilitate theenergy transfer to triplet oxygen. Biochemical and biophysical investigationsconfirmed that these photoactive chemical reagents can oxidativelyvary both metal-free amyloid-β (Aβ) and metal-bound Aβ,thereby redirecting their on-pathway aggregation into off-pathwayas well as disassembling their preformed aggregates. Moreover, thein vivo histochemical analysis of Aβ species produced upon photoactivationof the most promising candidate demonstrated that they do not aggregateinto oligomeric or fibrillar aggregates in the brain. Overall, ourcombined computational and experimental studies validate a light-basedapproach for designing small molecules, with minimum structural complexity,as chemical reagents targeting and controlling amyloidogenic peptidesassociated with neurodegenerative disorders.
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Journal	JACS Au
Volume Number	2
DOI	10.1021/jacsau.2c00281
PubMed Central reference number	PMC9516708
Issue Number	9
PubMed reference number	36186552
e-ISSN	26913704
Language	English
Publisher	American Chemical Society
Publisher Date	2022-08-11
Access Restriction	Open
Rights License	Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). © 2022 The Authors. Published by American Chemical Society
Subject Keyword	photosensitizers small molecules ESIHT amyloid-β peptide aggregation
Content Type	Text
Resource Type	Article
Subject	Chemistry Physical and Theoretical Chemistry Analytical Chemistry Organic Chemistry