Development of novel middle-molecule proteasome inhibitors and their drug delivery methods

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K05739
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: Nagahama Institute of Bio-Science and Technology
• Principal Investigator: Hasegawa Makoto 長浜バイオ大学, バイオサイエンス学部, 教授 (10367899)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 進化分子工学 / プロテアソーム阻害剤 / 中分子医薬

Outline of Final Research Achievements

The purpose of this study is to develop a peptide-conjugated inhibitor that can act easily on the 26S proteasome. This peptide region is permeable to cell membranes and enhances its effect on drug-resistant cells. First, we searched for novel sequence peptides that bind to membrane proteins prominently expressed in colorectal cancer by cDNA display method. Next, peptides that accumulate on proteasomes were linked to proteasome inhibitor compounds with a molecular weight of about 500, and compounds were synthesized that internalize cell-specifically by receptor endocytosis and accumulate on their targets. The drug efficacy was further demonstrated by using colon cancer-derived cell lines as a model system to verify intracellular proteasome activity and other properties.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

本研究では、プロテアソームの新しい制御機構を明らかにするために、ランダムペプチドライブラリーから20S PSに直接的な親和性を有するアミノ酸配列の探索を行った。得られたペプチドは、20S PSに対し非拮抗的に阻害作用を示した。その作用には疎水性アミノ酸を含む7残基の配列が重要であることを構造活性相関の検証により明らかにした。従来のプロテアソーム阻害剤が基質認識部位に直接作用するのに対し、これらのペプチドは全く異なるメカニズムで活性制御することから、新しいタイプのプロテアソーム阻害剤開発の手がかりになることが期待される。