title: Covalent modifier-type aggregation inhibitor of amyloid-β based on a cyclo-KLVFF motif.
abstract: Inhibition of amyloid-β (Aβ) aggregation could be a drug development target for treating Alzheimer disease. Insufficient activity to inhibit aggregation, however, remains a key issue. Here, we report a covalent modifier-type aggregation inhibitor of Aβ, diazirine-equipped cyclo-KLVF(β-Ph)F (2). Due to the affinity of the cyclo-KLVFF motif for Aβ, 2 selectively reacted with Aβ1-42 under UV-light irradiation to form an irreversible covalent bond. The Tyr-10 residue of Aβ1-42 was identified as the covalent modification site with 2. The extent of cross-β-sheet structure, characteristics of amyloid aggregation, and toxicity of Aβ1-42 were strongly attenuated by this chemical modification.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Ryuto
authors.initials: R
authors.lastname: Kino
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takushi
authors.initials: T
authors.lastname: Araya
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; ERATO (Japan) Science and Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tadamasa
authors.initials: T
authors.lastname: Arai
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; ERATO (Japan) Science and Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: ysohma@mol.f.u-tokyo.ac.jp.
authors.forename: Youhei
authors.initials: Y
authors.lastname: Sohma
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; ERATO (Japan) Science and Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: kanai@mol.f.u-tokyo.ac.jp.
authors.forename: Motomu
authors.initials: M
authors.lastname: Kanai
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology* / Q000648:ultrastructure; D000818:Animals; D002460:Cell Line; D003978:Diazomethane / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology* / Q000648:ultrastructure; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); C529399:amyloid beta-protein (16-20); D003978:Diazomethane
keywords: Aggregation; Alzheimer; Amyloid; Covalent modifier; Inhibitor