Covalent modifier-type aggregation inhibitor of amyloid-β based on a cyclo-KLVFF motif

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Kino, Ryuto¹  Araya, Takushi¹  Arai, Tadamasa^1,2  Sohma, Youhei^1,2  Kanai, Motomu^1,2 

[1] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan

[2] ERATO Japan Sci & Technol Agcy JST, Kanai Life Sci Catalysis Project, Bunkyo Ku, Tokyo 1130033, Japan

关键词: Aggregation;    Alzheimer;    Amyloid;    Covalent modifier;    Inhibitor;   

DOI  :  10.1016/j.bmcl.2015.05.027

来源: Elsevier

【 摘 要 】

Inhibition of amyloid-beta (A beta) 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 A beta, diazirine-equipped cyclo-KLVF(beta-Ph)F (2). Due to the affinity of the cyclo-KLVFF motif for A beta, 2 selectively reacted with A beta 1-42 under UV-light irradiation to form an irreversible covalent bond. The Tyr-10 residue of A beta 1-42 was identified as the covalent modification site with 2. The extent of cross-beta-sheet structure, characteristics of amyloid aggregation, and toxicity of A beta 1-42 were strongly attenuated by this chemical modification. (C) 2015 Published by Elsevier Ltd.

【 授权许可】

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