基于阿尔茨海默病药物分子的多肽类靶向载体的设计与合成研究

Alzheimer’s disease (AD) is the most common chronic and progressive form of neurodegenerative disease. The aggregation of increased levels of amyloid-β (Aβ) is believed to be critical in the aetiology of AD. Metal ions (e.g., Cu and Fe) found in Aβ plaques of the diseased brain can bind to Aβ and be linked to aggregation and neurotoxicity. The intersection of amyloid cascade hypothesis and implication of metal has been definitely recognized as a pathogenetic factor for AD. In this regard, compounds that can inhibit Aβ aggregation and/or bind the metal ions from the metal-Aβ species are considered rational therapeutic approaches for interdicting AD pathogenesis. However, the clinical or synthetic drugs at present are unlikely to cross the blood brain barrier, or long-term use of these drugs has a shortcoming because they are incapable of differentiating toxic metals associated with Aβ plaques from those associated with normal metal homeostasis. In this proposal, we attempt to prepare the monodisperse micelles with peptide for the drug-delivery to improve the efficacy of these therapeutic agents by increasing their solubility, extending their plasma half-life, increasing the amount of drug deposited in the desired tissue, and decreasing their exposure to healthy tissues. The proposed polypeptide micelles as the carriers can interact with the Aβ peptide and disassemble in the presence of β-secretase or hydroxyl radical, resulting in the release of drug in the desired tissue. We believe that our work would be valuable for developing a new therapeutic approach for AD.

阿尔茨海默病是全球患病率最高的一种神经退行性疾病，β-淀粉样肽（β-amyloid，Aβ）的异常代谢和聚集是导致该病的重要因素之一。金属离子（如铜和铁等）能够与Aβ键合，加速Aβ的聚集进程，诱导氧化应激的产生。最近，Aβ聚集阻断剂和金属螯合剂在阿尔茨海默病的治疗研究上取得了一定的进展，然而，当前临床试用和新开发的药物分子存在副作用大、靶向性差、对金属离子络合没有选择性或穿透血-脑屏障能力较差等问题。本项目拟设计一种两亲多肽纳米药物载体，用于阿尔茨海默病药物分子的靶向输送，从而提高药物分子的药效，降低药物的副作用。该纳米药物载体容易克服生理屏障、抵抗蛋白酶的水解，能够与Aβ发生特异性相互作用，在β-分泌酶或氢氧自由基的存在下可以降解成无毒的副产物，从而释放出药物分子。本项目有望在解决阿尔茨海默病药物治疗存在的高毒性、低效能等问题上取得突破性进展，为阿尔茨海默病的预防和治疗提供新的思路。

β-淀粉样肽（Aβ）是由跨膜蛋白依次经β及γ-分泌酶催化切割而成的，它的异常代谢和聚集是导致阿尔茨海默病的主要原因之一。本项目的主要研究内容是采用荧光光谱、原子力显微镜、电化学等手段研究Aβ的聚集过程及多肽自组装的条件，测定多肽在β-分泌酶存在条件下的稳定性，研究多肽、药物小分子、金属离子与不同Aβ片段的相互作用。该研究内容已经按计划执行并完成。此外，本项目研究还建立了不同形态的Aβ的检测方法，实现了与阿尔茨海默病相关的多种疾病标志物的灵敏检测，为阿尔茨海默病的早期诊断及药物治疗提供了重要手段和信息，对认识阿尔茨海默病的致病机理具有重要意义。