Studies on the opening mechanism of tight junction by MA026

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H02893
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 38040:Bioorganic chemistry-related
• Research Institution: University of Tsukuba
• Principal Investigator: Usui Takeo 筑波大学, 生命環境系, 教授 (60281648)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: タイトジャンクション / Claudin / 環状デプシペプチド / 構造活性相関

Outline of Final Research Achievements

MA026 is a natural product that reversibly opens tight junctions (TJs) in the epithelial barrier structure. In this study, the planar structure of natural MA026 was determined from biosynthesis gene analysis of the producing bacteria and total organic synthesis, and structure-activity relationships were investigated. The crystal structure revealed that MA026 has hydrophilic and hydrophobic amphiphilic surfaces, and that the amino acid cluster on the hydrophobic surface is important for the TJ opening. In addition, it was shown that this substance has high specificity for binding to the VFDSLL sequence of claudin-1, but also binds to the VFDSLL homologous sequence of claudin-3,4, which is expressed in the intestinal tract, suggesting the possibility that MA026 would be an oral substance permeation enhancer.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

MA026の可逆的TJ開口活性を利用することで、これまで注射などの侵襲的投与法を余儀なくされている難吸収性薬剤を、貼り薬や吸入剤といった経皮、経粘膜による非侵襲的手法で投与することが可能になると考えられる。今回の研究で明らかになった構造と活性の関係性や標的特異性は、高活性類縁体の合成へと展開でき、注射剤の経皮・経口薬への転換を可能にすることで、患者の薬剤投与への負担を軽減できるようになると期待される。