Structural elucidation of Wnt signaling mechanism using unique chemical tools

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H00455
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
• Research Institution: Osaka University
• Principal Investigator: Takagi Junichi 大阪大学, 蛋白質研究所, 教授 (90212000)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: Wntシグナル / ケミカルバイオロジー / 立体構造解析 / 環状ペプチド / アンタゴニスト

Outline of Final Research Achievements

This study aimed to elucidate the action mechanism of the Wnt signaling pathway, which is a key factor controlling the differentiation state of various tissue stem cells, using chemical biology tools. In the process, we developed a drug candidate, a neutralizing antibody against the endogenous Wnt inhibitor, USAG-1, and identified its epitope. Although we have already discovered a macrocyclic peptide binders to Wnt3a (PD04) that inhibited Wnt signaling, we applied a block-mutagenesis scanning display to identify a mutant inhibitor, WAp-D04-W10P, with 5-fold greater potency. This work represents for the first instance of molecules capable of inhibiting Wnt signaling through direct interaction with a Wnt protein.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

Wntシグナルは多細胞動物の発生・形態形成に必須なだけでなく、その異常はがんを含む様々な疾患に関わり、さらにはWntが組織幹細胞の生存と増殖に必須な増殖因子であることから再生医療を進めるためにも非常に重要な蛋白質である。本研究では、Wntシグナルを阻害することでがんに対する医薬のリードとなり得る環状ペプチド化合物の性質を詳細に調べるとともに、逆にWntシグナルを促進することで無歯症の治療に役立つ抗体の樹立とその作用原理の解明にも成功した。