Molecular interaction between ribosome-inactivating proteins and triterpene saponins

核糖体失活蛋白与三萜皂苷之间的分子相互作用

• 批准号: 422686308
• 负责人: Professor Dr. Alexander Weng
• 金额: --
• 依托单位: Institut für Pharmazie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422686308?language=en
• 关键词: Molecular; interaction; between; ribosome; inactivating

Ribosome-inactivating proteins (RIPs) are toxins that irreversibly inactivate the cellular protein machinery thus triggering cell death. RIPs are produced by certain plants that do also produce particular low molecular glycosides, which are termed triterpensaponins. Both components are sequestered within the plants’ seeds. We have shown that triterpensaponins massively increase the toxicity of RIPs. This effect relies on the ability of the triterpensaponins to drag the RIPs through biological membranes resulting in an increase of the cytosolic RIP concentration. In further studies we could demonstrate that the dragger function of triterpensaponins may be utilized for antibody-RIP-conjugates and non-viral gene delivery thus demonstrating the tremendous potential as platform technology for drug-delivery in general.Interaction analysis have shown that triterpensaponins bind to RIPs and further biophysical investigations indicate the formation of nanoparticulate triterpensaponin-RIP-complexes leading to an enhanced membrane penetration of the RIPs. It is hypothesized that this is facilitated by the formation of triterpensaponin-micelles encapsulating RIPs. Triterpensaponins are known to form micelles and micelles are in turn known to penetrate through biological membranes. The aim of the current project is to investigate the molecular interaction of triterpensaponins and RIPs. For this purpose in silico methods will be performed in order to identify the binding sites of the triterpensaponins on the RIP. By mutational approaches the appropriate binding sites will be than stepwise changed to non-binding sites. By using cell- and biophysical based methods the significance of these binding sites for the dragging function and the complex formation will be investigated.The basic insights provided by the results of this project might be the starting point for the development of novel innovative strategies to increase the intracellular delivery of drugs.

核糖体激活的蛋白质（RIPS）是毒素不可逆地使细胞蛋白质机制触发细胞死亡。 Trag在胞质RIP浓度的增加中拖动了tritterpensapons的A trage膜。进一步的生物物理投资e纳米式三角杆菌蛋白 - rip -compempemplexes导致裂口的膜增强为了通过使用基于细胞和生物物理的方法来鉴定tritterpensapons在RIP上的结合位点将被研究。该项目结果提供的基本见解可能是发展新型创新策略以增加药物的细胞内递送的新型创新策略的酸度。