金属ストレス下で活性化されるたんぱく質フォールディング促進剤の開発に成功～金属イオン捕捉とフォールディング促進の二刀流による変性疾患治療への展開へ期待～

2025-07-03 東京農工大学

図1　(a) 生体内のタンパク質フォールディングシステムのコンセプト図、(b) 本研究で開発した双機能性分子cyclam-SSによるタンパク質フォールディングのコンセプト図、(c) cyclam-SSの分子構造生体内では、タンパク質のミスフォールディングを誘発する細胞ストレスに応答してフォールディングシステムが活性化される。本研究で開発したcyclam-SSは金属イオン結合部位とフォールディング促進部位を併せ持つ双機能性分子であり、金属ストレス下でのタンパク質ミスフォールディング抑制と天然構造へのフォールディング促進を可能にした。

<関連情報>

• https://www.tuat.ac.jp/outline/disclosure/pressrelease/2025/20250703_01.html
• https://www.tuat.ac.jp/documents/tuat/outline/disclosure/pressrelease/2025/20250703_01.pdf
• https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202502187

タンパク質のミスフォールディングを抑制し酸化的フォールディングを促進する二官能性ジスルフィドの金属応答性アップレギュレーション Metal-Responsive Up-Regulation of Bifunctional Disulfides for Suppressing Protein Misfolding and Promoting Oxidative Folding

Keita Mori, Tsubura Kuramochi, Motonori Matsusaki, Yuki Hashiguchi, Masaki Okumura, Tomohide Saio, Yoshiaki Furukawa, Kenta Arai, Takahiro Muraoka
Angewandte Chemie International Edition  Published: 30 June 2025
DOI:https://doi.org/10.1002/anie.202502187

Abstract

The stress-responsive up-regulation process is a sophisticated biological response to maintain cellular homeostasis. In intracellular anti-oxidant systems, the expression level of oxidoreductases is up-regulated under oxidative stress, mitigating oxidative damage on biomolecules and enhancing protein folding capacity. Herein, inspired by the biological system, we developed a synthetic folding promotor whose reactivity is up-regulated under stress conditions. We conjugated two metal-binding 1,4,7,11-tetraazacyclotetradecane (cyclam) ligands and a redox-active disulfide to obtain cyclam-SS, whose reactivity can be enhanced under metal-induced stress. Metal coordination increased the redox potential of cyclam-SS, activating it as an oxidant. While Cu^II ions severely hampered the oxidative folding of substrate polypeptides, cyclam-SS exhibited bifunctional folding-promoting properties, i) suppressing Cu^II-mediated misfolding and aggregation, and ii) harnessing Cu^II to enhance oxidative folding. Cyclam-SS was also useful for disulfide-bond formation to promote oxidative folding of pharmaceutical and pathological proteins, as demonstrated with proinsulin and superoxide dismutase 1 (SOD1). Furthermore, cyclam-SS protected cultured cells from copper-induced stress. Thus, we demonstrated the induction of the stress-responsive up-regulation process by a bifunctional folding promotor controlling the folding status of biologically important proteins under metal-induced stress. The strategy of “stress-responsive up-regulation” could aid the development of novel synthetic materials for treating intracellular stress and related disorders.