抗KRAS環状ペプチドファマコフォアの小型タンパク質へのラソグラフト体の創出

将抗 KRAS 环肽药效基团移植到小蛋白质上

• 批准号: 22KF0089
• 负责人: 菅 裕明
• 金额: $ 1.47万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2023
• 资助国家: 日本
• 起止时间: 2023-03-08 至 2024-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-22KF0089/
• 关键词: KRas; lasso-graft; macrocylic peptides; RaPID

Two anti-KRas peptides (KD2 and KWT9) have been grafted to Ubiquitin to provide two initial generations of hybrid constructs called “Ubodies” with different selectivity profiles. KD2-derived Ubodies are selective for the KRas “on” vs “off” state. KWT9 is newly identified, and displays (together with its Ubody derivatives) selectivity towards the mutant KRas over the healthy protein. A further generation of de novo Ubodies was also developed. Initial evaluation shows several hit compounds featuring excellent activity on the malignant target protein and selectivity over the healthy protein and/or the “off” state. Early results from collaborators validate the potential of the peptides, although further experimental work is needed on the Ubodies. The overall workflow for Ubody development has now been streamlined, from peptide hit identification, lasso-graft tether optimization, expression and purification to binding kinetics estimation. This experimental scheme can now be applied to different targets. The main challenge remaining to this project is now the delivery of the Ubodies into the cell by viral vector transfection.

两种抗Kras肽（KD2和KWT9）已移植，以提供两个称为“ Ubodies” H不同的选择性概况的氢肽鉴定出（与使用衍生物）对NOV的能量的选择性也得到了选择。在Ubodies上需要进一步的实验性工作。细胞矢量传递。