Design, synthesis, and evaluation of Trolox-conjugated amyloid-β C-terminal peptides for therapeutic intervention in an in vitro model of Alzheimer’s disease

• Published in: Bioorganic & medicinal chemistry 2016-09, Vol.24 (18), p.4138-4143
• Main Authors: Arai, Takuya, Ohno, Akiko, Kazunori, Mori, Kakizawa, Taeko, Kuwata, Hiroshi, Ozawa, Toshihiko, Shibanuma, Motoko, Hara, Shuntaro, Ishida, Seiichi, Kurihara, Masaaki, Miyata, Naoki, Nakagawa, Hidehiko, Fukuhara, Kiyoshi
• Format: Article
• Language: English
• Subjects: Aggregation inhibitor; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - pharmacology; Amyloid-β; Antioxidants - chemistry; Antioxidants - pharmacology; Antioxidative activity; C-terminal motif; Cell protection; Chromans - chemistry; Chromans - pharmacology; Drug Design; Humans; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Protein Aggregates - drug effects; Reactive Oxygen Species - metabolism; Trolox
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.06.057

[Display omitted] 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.