淀粉样蛋白聚集的机理研究和抑制剂的设计、合成与评价
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摘要
淀粉样蛋白的错误折叠和异常聚集通常被认为是阿兹海默症、2型糖尿病、朊病毒蛋白相关疾病等淀粉样变性病的主要致病原因之一。由于淀粉样蛋白聚集的重要性,对于淀粉样蛋白聚集机理以及聚集抑制剂的研究被视为是推进相关疾病药物研发和临床治疗的关键方向之一。在本论文中，我们重点研究了淀粉样蛋白的聚集机理，以及针对一价铜导致聚集的相关抑制剂的合成，这些工作将为我们在相关领域的进一步研究提供支持。
我们选用胰岛淀粉样蛋白和朊蛋白片段106-126作为淀粉样蛋白聚集机理研究的模型。对于胰岛淀粉样蛋白，我们通过原子力显微镜和微秒力显微镜发现胰岛淀粉样蛋白能够在五氧化二钽表面形成环状聚集体，并推断出环状聚集体的生长模型。通过进一步研究胰岛淀粉样蛋白及其衍生物的碳末端基团对它们的性质的影响，我们发现碳末端酰胺化的天然胰岛淀粉样蛋白与碳末端未酰胺化的胰岛淀粉样蛋白衍生物在聚集速度、聚集体构成、细胞毒性等方面存在明显差异。天然的胰岛淀粉样蛋白能迅速发生聚集，跨越有毒的寡聚体状态。而未酰胺化的胰岛淀粉样蛋白衍生物初始聚集速度较慢，在有毒的寡聚体状态持续时间较长，并最终生成β-折叠含量较高的纤维状聚集体。这些差异可能是由于蛋白在疏水核心区、构象等方面的差异导致的。我们通过计算机分子动力学模拟验证了上述的结果。对于朊蛋白片段106-126，我们通过原子力显微镜发现随着孵育时间的增长，蛋白能够形成非常密集的网膜状结构。我们推断正是这些网膜状结构侵占正常神经元生长的空间，从而导致神经元损伤。我们进一步发现盐酸和乙醇两种溶剂都能够加速网膜状结构的生成，从而推断环境因素可能对朊蛋白的聚集有巨大影响。这为进一步的机理研究和未来的药物开发奠定了基础。
基于淀粉样蛋白聚集机理的基础性研究工作，我们选用β-淀粉样蛋白Aβ1-40作为蛋白模型，设计并合成出由硫代黄素T衍生出来的小分子抑制剂。该小分子抑制剂可以抑制淀粉样蛋白聚集过程中出现的过量一价铜离子，阻止恶性的氧化还原循环，从而达到保护细胞的目的。这为治疗铜介导的淀粉样蛋白错误折叠所造成的疾病提供了新的策略。
The misfolding and abnormal aggregation of proteins is usually believed as onemain contributing factor of several amyloid diseases, such as Alzheimer’s disease, type2diabetes and prion diseases. Due to the importance of amyloid fibrillization,investigating the underlying mechanism of amyloid protein aggregation and designingappropriate inhibitors have been considered as a promising approach to advance theclinical treatment of these diseases. However, though lots of efforts have beencontributed to related researches on amyloid proteins, the mechanism of amyloidaggregation is still not fully understood. In this thesis, we investigated the aggregationmechanism of amyloid proteins, and designed inhibitors to block the copper-mediatedamyloid aggregation. These works could provide us further insights in relevant areas.
Amylin and prion106-126were selected as the protein models to study theassembly mechanisms. For amylin, we studied the annular structure of amylin onnegatively-charged Tantalum oxide surface through atomic force microscopy andmicrosecond force spectroscopy, based on which we proposed an accumulation modelon how annular aggregation is initiated and developed. We further investigated theimpacts of C-terminus on amylin assembly and found that the difference at C-terminalregion between natural amylin and an amylin variant could result in different assemblypathways and different composition of the aggregates by influencing the hydrophobiccore, conformations, and intra-sheet interactions of peptides. The differences in theassembly processes further characterize the differences in cytotoxicity.
For prion106-126, we applied atomic force microscopy to study the aggregation ofprion106-126in different solvents and found that the aggregated prion106-126fibrilscould form highly crowded membrane-like structures, which may occupy the space ofneurons and induce neuron death. Furthermore, we found that HCl and ethanol mightaccelerate prion aggregation and aggravate related negative impacts. Therefore, wepropose that environmental factors may influence the aggregation process of prionprotein. The works on amylin and prion aggregation provides us new clues for furthermechanism studies and drug design.
Based on the investigation of amyloid aggregation mechanism, we designed smallmolecule inhibitors to target the copper-mediated amyloid aggregation. The designedinhibitors can chelate Cu(I) from the aberrant copper redox cycle, and thus protect cells against Aβ induced neurotoxicity. Our approach on inhibitor design may lead to analternative strategy for developing therapeutic drugs for Cu-mediated protein diseases.
我们选用胰岛淀粉样蛋白和朊蛋白片段106-126作为淀粉样蛋白聚集机理研究的模型。对于胰岛淀粉样蛋白，我们通过原子力显微镜和微秒力显微镜发现胰岛淀粉样蛋白能够在五氧化二钽表面形成环状聚集体，并推断出环状聚集体的生长模型。通过进一步研究胰岛淀粉样蛋白及其衍生物的碳末端基团对它们的性质的影响，我们发现碳末端酰胺化的天然胰岛淀粉样蛋白与碳末端未酰胺化的胰岛淀粉样蛋白衍生物在聚集速度、聚集体构成、细胞毒性等方面存在明显差异。天然的胰岛淀粉样蛋白能迅速发生聚集，跨越有毒的寡聚体状态。而未酰胺化的胰岛淀粉样蛋白衍生物初始聚集速度较慢，在有毒的寡聚体状态持续时间较长，并最终生成β-折叠含量较高的纤维状聚集体。这些差异可能是由于蛋白在疏水核心区、构象等方面的差异导致的。我们通过计算机分子动力学模拟验证了上述的结果。对于朊蛋白片段106-126，我们通过原子力显微镜发现随着孵育时间的增长，蛋白能够形成非常密集的网膜状结构。我们推断正是这些网膜状结构侵占正常神经元生长的空间，从而导致神经元损伤。我们进一步发现盐酸和乙醇两种溶剂都能够加速网膜状结构的生成，从而推断环境因素可能对朊蛋白的聚集有巨大影响。这为进一步的机理研究和未来的药物开发奠定了基础。
基于淀粉样蛋白聚集机理的基础性研究工作，我们选用β-淀粉样蛋白Aβ1-40作为蛋白模型，设计并合成出由硫代黄素T衍生出来的小分子抑制剂。该小分子抑制剂可以抑制淀粉样蛋白聚集过程中出现的过量一价铜离子，阻止恶性的氧化还原循环，从而达到保护细胞的目的。这为治疗铜介导的淀粉样蛋白错误折叠所造成的疾病提供了新的策略。
The misfolding and abnormal aggregation of proteins is usually believed as onemain contributing factor of several amyloid diseases, such as Alzheimer’s disease, type2diabetes and prion diseases. Due to the importance of amyloid fibrillization,investigating the underlying mechanism of amyloid protein aggregation and designingappropriate inhibitors have been considered as a promising approach to advance theclinical treatment of these diseases. However, though lots of efforts have beencontributed to related researches on amyloid proteins, the mechanism of amyloidaggregation is still not fully understood. In this thesis, we investigated the aggregationmechanism of amyloid proteins, and designed inhibitors to block the copper-mediatedamyloid aggregation. These works could provide us further insights in relevant areas.
Amylin and prion106-126were selected as the protein models to study theassembly mechanisms. For amylin, we studied the annular structure of amylin onnegatively-charged Tantalum oxide surface through atomic force microscopy andmicrosecond force spectroscopy, based on which we proposed an accumulation modelon how annular aggregation is initiated and developed. We further investigated theimpacts of C-terminus on amylin assembly and found that the difference at C-terminalregion between natural amylin and an amylin variant could result in different assemblypathways and different composition of the aggregates by influencing the hydrophobiccore, conformations, and intra-sheet interactions of peptides. The differences in theassembly processes further characterize the differences in cytotoxicity.
For prion106-126, we applied atomic force microscopy to study the aggregation ofprion106-126in different solvents and found that the aggregated prion106-126fibrilscould form highly crowded membrane-like structures, which may occupy the space ofneurons and induce neuron death. Furthermore, we found that HCl and ethanol mightaccelerate prion aggregation and aggravate related negative impacts. Therefore, wepropose that environmental factors may influence the aggregation process of prionprotein. The works on amylin and prion aggregation provides us new clues for furthermechanism studies and drug design.
Based on the investigation of amyloid aggregation mechanism, we designed smallmolecule inhibitors to target the copper-mediated amyloid aggregation. The designedinhibitors can chelate Cu(I) from the aberrant copper redox cycle, and thus protect cells against Aβ induced neurotoxicity. Our approach on inhibitor design may lead to analternative strategy for developing therapeutic drugs for Cu-mediated protein diseases.
引文
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