title: Design, synthesis, and evaluation of Trolox-conjugated amyloid-β C-terminal peptides for therapeutic intervention in an in vitro model of Alzheimer's disease.
abstract: Two hallmarks of Alzheimer's disease (AD) observed in the brains of patients with the disease include oxidative injury and deposition of protein aggregates comprised of amyloid-β (Aβ) variants. To inhibit these toxic processes, we synthesized antioxidant-conjugated peptides comprised of Trolox and various C-terminal motifs of Aβ variants, TxAβx-n (x=34, 36, 38, 40; n=40, 42, 43). Most of these compounds were found to exhibit anti-aggregation activities. Among them, TxAβ36-42 significantly inhibited Aβ1-42 aggregation, showed potent antioxidant activity, and protected SH-SY5Y cells from Aβ1-42-induced cytotoxicity. Thus, this method represents a promising strategy for developing multifunctional AD therapeutic agents.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan; School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Arai
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Ohno
authors.affiliation: School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Mori
authors.initials: M
authors.lastname: Kazunori
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Kakizawa
authors.affiliation: School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuwata
authors.affiliation: Division of Oxidative Stress Research, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida-shi, Tokyo 194-8543, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Shibanuma
authors.affiliation: School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Hara
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Ishida
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kurihara
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. Electronic address: fukuhara@pharm.showa-u.ac.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukuhara
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002839:Chromans; D010446:Peptide Fragments; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); C000621368:amyloid beta-protein (36-42); C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
keywords: Aggregation inhibitor; Alzheimer’s disease; Amyloid-β; Antioxidative activity; C-terminal motif; Cell protection; Trolox