O-アシルイソペプチド法を基盤とした“Click Peptide” の開発:アルツハイマー病に関連するdifficult sequence含有Aβ1-42変異体の合成

相馬 洋平; 千代森 陽介; 谷口 敦彦; 木村 麻衣子; 深尾 福栄; 林 良雄; 木村 徹; 木曽 良明

doi:10.14895/hannou.31.0.94.0

31th Synposium on Progress in Organic Reactions and Syntheses

Session ID : 1P-41

DOI https://doi.org/10.14895/hannou.31.0.94.0

Conference information

Host: Division of Organic Chemistry, The Pharmaceutical Society of Japan

"Click Peptide" Based on the O-Acyl Isopeptide Method: Synthesis of Difficult Sequence-Containing Alzheimer's Disease-Related Aβ1-42 Mutants

Youhei Sohma, Yousuke Chiyomori, *Atsuhiko Taniguchi, Maiko Kimura, Fukue Fukao, Yoshio Hayashi, Tooru Kimura, Yoshiaki Kiso

Author information

Youhei Sohma
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and Physical Chemistry,21st Century COE Program, Kyoto Pharmaceutical University
Yousuke Chiyomori
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and Physical Chemistry,21st Century COE Program, Kyoto Pharmaceutical University
*Atsuhiko Taniguchi
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and Physical Chemistry,21st Century COE Program, Kyoto Pharmaceutical University
Maiko Kimura
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and Physical Chemistry,21st Century COE Program, Kyoto Pharmaceutical University
Fukue Fukao
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and Physical Chemistry,21st Century COE Program, Kyoto Pharmaceutical University
Yoshio Hayashi
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and Physical Chemistry,21st Century COE Program, Kyoto Pharmaceutical University
Tooru Kimura
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and Physical Chemistry,21st Century COE Program, Kyoto Pharmaceutical University
Yoshiaki Kiso
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and Physical Chemistry,21st Century COE Program, Kyoto Pharmaceutical University

Keywords: O-acyl isopeptide method, Alzheimer's disease, Aβ1-42 mutant, click peptide, difficult sequence

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Abstract

The highly agglutinative feature of Aβ1-42 is a significant obstacle for establishing a reliable in vitro biological experiment system to investigate the major causative agents of Alzheimer's disease (AD) and its related diseases. To solve this problem, based on the O-acyl isopeptide method, we have developed novel pH-triggered "click peptides" of wild- and mutant-type Aβ1-42s, "26-O-acyl isoAβ1-42s (26-AIAβ42s)". These isopeptides suppressed the agglutinative nature of each Aβ1-42 with only one insertion of the isopeptide structure, and could migrate to the corresponding Aβ1-42 quickly via pH-dependent O-N intramolecular acyl migration reaction (by pH-triggered "click"). The method would provide a novel biological evaluation system in AD-related research, in which 26-AIAβ42 can be stored in a solubilized form and rapidly produces intact Aβ1-42 in situ during biological experiments.

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