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.

核糖体失活蛋白（RIP）是一种毒素，它不可逆地破坏细胞蛋白质机制，从而引发细胞死亡。RIP是由某些植物产生的，这些植物也产生特定的低分子糖苷，称为三萜皂苷。这两种成分都被隔离在植物的种子中。我们已经表明，三萜皂苷大大增加RIP的毒性。这种作用依赖于三萜皂苷拖动RIP通过生物膜的能力，导致细胞溶质RIP浓度的增加。在进一步的研究中，我们可以证明三萜皂苷的拖曳功能可以用于抗体-RIP-缀合物和非病毒基因递送，从而证明作为药物递送的平台技术的巨大潜力。复合物导致RIP的膜渗透增强。据推测，这是由封装RIP的三萜皂苷胶束的形成促进的。已知三萜皂苷形成胶束，并且胶束进而已知穿透生物膜。本课题的目的是研究三萜皂苷与RIPs的分子相互作用。为此，将进行计算机模拟方法，以鉴定RIP上三萜皂苷的结合位点。通过突变方法，适当的结合位点将逐步变为非结合位点。通过使用细胞和生物物理为基础的方法的意义，这些结合位点的拖动功能和复合物的形成将investigated.The基本的见解提供了这个项目的结果可能是新的创新策略，以增加药物的细胞内输送的发展的起点。