Novel innovations in cytoplasmic delivery peptides directed at intracellular delivery of antibodies

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15250
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Kyoto University
• Principal Investigator: Kawaguchi Yoshimasa 京都大学, 化学研究所, 助教 (90936808)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: ペプチド / 抗体 / 細胞内送達 / 細胞質 / 膜傷害性ペプチド / コンジュゲート / エンドサイトーシス / エンドソーム脱出

Outline of Final Research Achievements

In this study, we developed E3MPH16, which has a wide safety margin and highly efficient cytosolic delivery derived from mastoparan X, and showed that anti-Ras antibody delivered by E3MPH16 into HT1080 cells inhibited their growth. Furthermore, topical administration of NLS-EGFP and E3MPH16 to tumor-bearing mice showed that NLS-EGFP could be delivered to the cytosol in some cells. We also examined the preparation of conjugates of L17ER4, an intracellular delivery peptide, with antibodies. We showed that the conjugates could be prepared by the enzyme-chemical method using sortase, and the antibodies could be delivered to the cytosol without aggregation. The application of the conjugation method to various peptides will lead to more efficient cytosolic delivery of antibodies and will be a fundamental technology in vivo delivery, and it is expected to lead to practical drug discovery research efforts in the future.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

今回開発したE3MPH16は低毒性かつ高効率で高分子を細胞質に送達可能なペプチドであることから、機能性高分子の細胞質送達に有用であると考えられる。また、in vivoでも送達可能であったことから、今後、抗体の細胞質送達による細胞機能制御への展開が期待される。また、L17E４と抗体のコンジュゲート設計を達成したことから、このコンジュゲーション方法を様々なペプチドに応用することで、より効率的な抗体の細胞質送達につながるとともに、in vivoでのデリバリーにおける基盤技術になると考えられ、今後、創薬研究への実践的取り組みにつながると期待される。