title: Synthesis of a potent photoreactive acidic γ-secretase modulator for target identification in cells.
abstract: Supramolecular self-assembly of amyloidogenic peptides is closely associated with numerous pathological conditions. For instance, Alzheimer´s disease (AD) is characterized by abundant amyloid plaques originating from the proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Compounds named γ-secretase modulators (GSMs) can shift the substrate cleavage specificity of γ-secretase toward the production of non-amyloidogenic, shorter Aβ fragments. Herein, we describe the synthesis of highly potent acidic GSMs, equipped with a photoreactive diazirine moiety for photoaffinity labeling. The probes labeled the N-terminal fragment of presenilin (the catalytic subunit of γ-secretase), supporting a mode of action involving binding to γ-secretase. This fundamental step toward the elucidation of the molecular mechanism governing the GSM-induced shift in γ-secretase proteolytic specificity should pave the way for the development of improved drugs against AD.
authors.affiliation: Research Group Chemical Biology of Neurodegenerative Diseases, Center of Advanced European Studies and Research, Ludwig-Erhard-Allee 2, D-53175 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rennhack
authors.forename: Thorsten
authors.initials: T
authors.lastname: Jumpertz
authors.forename: Julia
authors.initials: J
authors.lastname: Ness
authors.forename: Sandra
authors.initials: S
authors.lastname: Baches
authors.forename: Claus U
authors.initials: CU
authors.lastname: Pietrzik
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.forename: Bruno
authors.initials: B
authors.lastname: Bulic
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D001389:Azirines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000528:radiation effects; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D055668:Photochemical Processes / Q000528:radiation effects; D013329:Structure-Activity Relationship
chemical_list: D001389:Azirines; D053829:Amyloid Precursor Protein Secretases