| Project/Area Number |
16K08329
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | Nagahama Institute of Bio-Science and Technology |
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Principal Investigator |
Hasegawa Makoto 長浜バイオ大学, バイオサイエンス学部, 教授 (10367899)
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| Project Period (FY) |
2016-10-21 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | プロテアソーム阻害剤 / 膜透過ペプチド / 薬剤耐性骨髄腫 / 膜透過性ペプチド / 分子進化工学 / 中分子医薬 / ケミカルバイオロジー |
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| Outline of Final Research Achievements |
Ridaifen-F (RID-F) potently inhibits proteolytic activities of the 20S proteasome but poorly inhibits those of the 26S proteasome. We prepared several conjugates in which various peptides are connected to RID-F. Conjugates with peptides consisting of seven amino acid residues significantly inhibited the 26S proteasome. Particularly, RID-F conjugated to an octaarginine peptide inhibited intracellular proteasome activities and induced cell death in drug-resistant KMS-11 myeloma cells. We infer that the R8 peptide has dual functions: (1) rapid penetration of conjugates into the cell increases intracellular drug concentrations sufficient for exhibition of its effect, and (2) recognition of the conjugates by the 26S proteasome stimulates drug entry into the catalytic chamber. Thus, conjugation of nonpeptidic proteasome inhibitors with a cell-penetrating peptide a viable strategy to overcome drug-resistance of tumor cells.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、新規化合物リダイフェン-F (RID-F)の構造活性相関を検討した結果、阻害活性の最小構造を見出した。RID-Fは、ヒト培養細胞に対してユビキチン修飾タンパク質の蓄積とアポトーシス誘導を引き起こした。しかし、その効果は比較的高容量を必要とした。そこで、RID-Fに細胞膜透過ペプチドの付加を検討した。これは細胞膜透過のみならず26Sプロテアソームに対する阻害活性を増強し、多剤耐性を示す骨髄腫細胞株に対して細胞死を誘導した。以上の結果から、薬効改善のための合理的な構造デザイン法を提示し、中程度の分子量を持つ化合物による新しい創薬の戦略を提示した。
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