Proposal of a New Drug Discovery Concept Enabling Membrane Protein Knockdown

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K19054
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 37:Biomolecular chemistry and related fields
• Research Institution: Kyushu University
• Principal Investigator: Mori Takeshi 九州大学, 工学研究院, 准教授 (70335785)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Keywords: ケミカルノックダウン / 膜タンパク質 / エンドサイトーシス

Outline of Final Research Achievements

The objective of this study was to develop a protein knockdown technique for membrane proteins. Milestones include the development of appropriate transmembrane and clathrin recognition sites. We focused on acidic pH-responsive peptides as transmembrane parts. The existing peptide (pHLIP) is of bacterial origin, and its antigenicity is of concern. Therefore, we searched the human proteome for pHLIPs. pHLIPs were searched for the transmembrane region of all transmembrane proteins as candidates (more than 100,000 species) by listing the characteristics of pHLIPs and using these as necessary conditions, about 20 peptides satisfied the conditions. Of these, four peptides were evaluated, and one of them showed cell-accumulating ability equivalent to pHLIP. In the future, we aim to develop the clathrin recognition part and realize the technology.

Free Research Field

医用化学

Academic Significance and Societal Importance of the Research Achievements

がんをはじめとする様々な疾患の原因はタンパク質にあり、標的タンパク質を自在に破壊（ノックダウン）する技術の開発は、これら疾患の治療薬となるのみならず、それらのタンパク質の生物学的な機能を明らかにすることができる。これまで、細胞内のタンパク質に対するノックダウン技術が開発されてきたが、膜タンパク質に対する開発は遅れていた。本研究ではこれを目指し、最初のマイルストンである膜貫通部のペプチドを見出すことに成功した。