基于立百病毒受体复合物的脑靶向载药多肽设计

Receptor-mediated endocytosis(RME) is a promising approach of brain targeting drug delivery. It is the key for RME to find the ideal receptor on blood brain barrier and to design its ligand. Nipah virus is an emergent paramyxovirus that causes fatal encephalitis. EphrinBs, the membrane-bound receptor expressed on endothelial cells and neurons, specifically binds to the attachment (G) glycoprotein of NiV and finally lead to central nervous system infection. In this proposal, based on the complex structure data of NiV-G/EphrinBs complex, we plan to employ molecular dynamics simulation, binding free energy prediction and protein-protein docking calculation to study the interaction between NiV and its receptor, and determine the key residues which are important for the binding to NiV-G receptors. The peptide with those key residues may show similar cell tropism with virus, and can be used as the homing devices of brain targeted drug delivery system. Applying molecular simulation method systematically to study the virus-viral receptor interactions and designing the drug delivery system base on those interactions has not been reported yet. Such study is the original work. We have designed a novel series of anti-tumor peptides by predicting the interaction between proteins and designed a feasible protocol to optimize the peptide. Those experiences will help us to design the viral receptor binding peptide.

受体介导内吞的脑靶向是一种很有发展前途的主动靶向中枢药物转运方式。找到合适的中枢受体并设计得到有效的配体，是通过这一途径开发中枢靶向药物传递系统的关键环节。立百病毒可通过与中枢受体形成特异性结合侵入脑组织，引起高致死率的病毒性脑炎，有很明显的中枢嗜性。本项申请提出以立百病毒G糖蛋白及其中枢受体EphrinBs蛋白复合物为研究对象，应用分子动力学模拟，结合自由能预测和蛋白质对接等方法，找到蛋白质识别的关键残基，设计，优化并合成具有中枢靶向性的载药多肽，模拟立百病毒的中枢嗜性，实现基于病毒受体的脑靶向载药。基于病毒-病毒受体复合物结构，系统性地应用计算机辅助药物设计手段开展靶向载药系统的研究，目前尚没有报道，具有创新性。在以往的研究中，我们曾经应用相同方法模拟了细胞凋亡信号相关蛋白，所设计的抗肿瘤多肽表现出良好的活性，相信这些经验能够帮助我们得到理想的载药多肽。

中枢神经系统疾病的治疗一直是医学领域的重要问题。目前，由于许多药物不能透过血脑屏障或通过量很少，达不到控制疾病的作用。 为了解决上述问题，本课题以嗜神经性的病毒为研究对象，截取和筛选病毒结合贡献的多肽为脑靶向分子，将其修饰于药物递送系统中，实现脑靶向药物递释。主要工作有以下几个方面：.1、以立百病毒为研究对象，截取和筛选病毒 NiV-G糖蛋白上有结合贡献的序列，经过虚拟突变优化，确定了最终序列，实现脑靶向药物递释。.2、以马丘波病毒为研究对象，截取和筛选病毒 G1 糖蛋白上有结合贡献的序列，经过虚拟突变优化，确定了最终序列。.3、以狂犬病毒为研究对象，截取和筛选病毒RVG糖蛋白上有结合贡献的序列，经过虚拟突变优化，确定了最终序列。