金属配合物与朊蛋白神经肽的相互作用

Prion disease is a kind of neurodegenetive disorder, which is induced by the conformational change of prion protein. With the increasing of the incidence, this disease seriously influences human being's health, and no effective therapeutics are found out until now. The nosogenesis of prion disease is thought to be ralative with the aggregation of an aberrant conformational isomer of prion protein, PrPSc. Hence, it will be an important pathway of drug design to explore the effective chemical compounds that inhibit protein aggregation. .The human prion neuropeptide PrP106-126, has similar physiological characteristics and bioactivities with aberrant prion protein PrPSc, which is an ideal model to invesitigate the structural and functional relationship of prion protein. In our former work, some metal complexes were revealed to well interact with PrP106-126 and inhibit the aggeragation of this neuropeptide. However, it is still unclear that how the ligands property and their configurations affact the binding affinity and aggregation between metal complexes and PrP106-126..In the present project, some mothods including NMR, ESI-MS and fluorescence spectrometry will be used to investigate the interaction between different metal complexes and PrP126-126 as well as its mutants. The effects of ligand property and key residues on the binding affinity and aggregation of PrP106-126 will be elucidated. These will reveal the interaction mechanism of prion neuropeptide with metal complexes. The research results are of great importance in design and development of highly effective metallodrugs against prion disease.

朊病毒病是由蛋白构象变化引起的一类神经退行性疾病，该病发病率不断增加,但尚无有效治疗方法。朊病毒病的发生被认为与致病型朊蛋白PrPSc的聚集有关, 因而寻求能有效抑制朊蛋白聚集的金属药物是治疗朊病毒病的重要研发思路。人朊蛋白神经肽 PrP106-126与致病型朊蛋白PrPSc具有相似的理化性质和生物活性，是研究朊蛋白的理想模型。前期工作中我们发现一些金属配合物与PrP106-126有较好的结合作用并有效抑制了神经肽的聚集，但是配体性质、配体构型如何影响金属配合物与神经肽PrP106-126的结合机制及抑制聚集机理还不清楚。本课题拟通过多种谱学手段研究不同配体的金属配合物与PrP106-126及其突变体的相互作用，探索配体构型和关键氨基酸对金属配合物-神经肽结合作用及神经肽聚集性质的影响，揭示金属配合物与朊蛋白神经肽的结合方式及抑制多肽聚集的作用机制，该研究对发展潜在金属药物具有重要意义。

淀粉样蛋白构象病包括阿尔兹海默症, 帕金森症, 朊病毒病等神经退行性疾病。朊病毒病在人与动物体内均有发生，其致病机制与朊蛋白的错误折叠和淀粉样纤维化有关。朊蛋白神经肽PrP106-126与致病型朊蛋白具有很大的相似性，因而成为朊病毒症潜在药物的作用靶标。本项目主要研究以金、钌配合物为代表的不同构型金属配合物与朊蛋白神经肽PrP106-126的相互作用，通过核磁共振、电喷雾质谱、循环伏安法等探讨了不同构型的配合物与多肽的结合亲和性，以及可能的结合方式与结合位点，获得了以不同金属离子为中心的配合物与神经肽的结合特征，以及配位原子和配体构型差异产生的对结合方式的影响；并研究了部分配合物与一些神经肽突变体和类似片段的作用机制，比较了不同神经肽片段的聚集性和结合性；通过荧光分析、形貌成像以及细胞检测等方法研究了配合物对PrP106-126聚集纤维化的抑制作用和细胞毒性的调节作用；揭示了金属配合物作为潜在淀粉样变性相关疾病药物的可能性。本项目按照研究计划顺利完成，达到了预期的目标。