针对蛋白质聚集的抑制剂调控机制的动力学研究

Protein aggregation and fibrillation is closely related to many important neurodegenerative diseases, like Alzheimer's, Parkinson's and Huntington's diseases. By choosing proper inhibitors, such as natural animal and plant extracts, antibodies, chaperons and nanoparticles, we can slow down the aggregation of amyloid proteins, reduce the cytotoxicity of aggregates and protect neurons. However, for many inhibitors, their modulation mechanisms on protein aggregation are still unknown. In the current study, based on chemical kinetics, we plan to perform systematic explorations on various modulation mechanisms of inhibitors. Through mathematical modeling, analysis and numerical simulations, the effects of inhibitor concentration and association rate will be quantified under conditions of both fixed and varied protein concentrations. Furthermore, to overcome the shortcomings of unilateral inhibitors and achieve synergistic effect, we are going to design compound inhibitors against Aβ aggregation. The ingredients of a compound inhibitor will be determined by taking advantage of chemical kinetic analysis, as well as physico-chemical properties and structural information of inhibitors. Our work will shed new light on the development of Alzheimer's drugs, medications and therapies.

蛋白质聚集及纤维化与许多重要的神经退行性疾病相关，如阿尔兹海默症、帕金森症、亨廷顿症等。研究表明通过选择适当的抑制剂，如一些动植物提取物、抗体、分子伴侣、纳米颗粒等，可以有效地阻抑蛋白质的聚集过程，降低蛋白质纤维对细胞的毒性。然而目前许多抑制剂的分子调控机制尚不清楚。针对这一困难，本项目拟基于化学反应动力学，通过数学建模、分析和数值计算，对抑制剂的调控机制展开系统的研究。针对蛋白质浓度固定和浓度改变两种不同条件，定量刻画抑制剂浓度、结合速率等参数对调控作用的影响。为了克服传统单一成分抑制剂广谱性差、无法阻断交叉成核过程的缺点，我们将进一步设计针对Aβ蛋白质的混合型抑制剂。基于动力学分析结果，并综合考虑抑制剂的理化性质和结构参数，我们将确定合适的抑制剂成分及配比，通过协同作用来达到对Aβ蛋白质聚集过程的全面抑制。我们的工作将为阿尔兹海默症相关药物和治疗方法的研究提供新的思路和指导。

蛋白质聚集与许多重要的神经退行性疾病相关，如阿尔兹海默症、帕金森症、亨廷顿症等。以往研究表明合适的抑制剂，如动植物提取物、抗体、分子伴侣、纳米颗粒等，可以有效地阻抑蛋白质的聚集过程，降低蛋白质聚集对细胞的毒性。然而目前为止许多抑制剂的分子调控机制并不清楚。针对这一困难，本项目组：（1）合作开发了包括葫芦脲、黑磷烯、海参多糖等在内的多种Aβ多肽聚集抑制剂，首次阐明了上述抑制剂的分子作用机制，并定量刻画了蛋白质浓度、抑制剂浓度、结合速率等参数对调控作用的影响；（2）基于动力学分析，并综合考虑抑制剂的理化性质和结构参数，设计开发了针对Aβ多肽聚集的新型复方抑制剂，明确了抑制剂成分及合理配比。该复方抑制剂克服了传统单一成分抑制剂广谱性差、无法阻断交叉成核过程等缺点，实现了对Aβ多肽聚集过程的全面抑制。本项目研究结果不仅提供了若干种潜在的阿尔兹海默症治疗药物，澄清了相关药物的分子作用机理，而且为开发新型复方治疗药物和治疗方法提供了思路和理论指导。