共价/非共价Polo-like Kinase 2抑制剂的设计、合成及其抗帕金森氏症的机理研究

Parkinson’s disease (PD) is a degenerative disorder of the central nervous system which severely threatens the health and lives of the elderly. Drug therapy is the main treatment for PD, whereas, it can only improve symptom but could not stop the progression of the disease or cure the disease. Recent discoveries have implicated Plk-2 as a major contributor to the formation of pS129 a-synuclein and thus, inhibitors of Plk-2 have the potential to be useful therapeutics for the treatment of PD and related Lewy body diseases. However few selective Plk-2 inhibitors have been reported up to date. In this proposal, based on the selective Plk-2 inhibitors developed by our lab, structure-based drug design techniques will be taken to design novel and potent irreversible (or covalent) selective Plk-2 inhibitors. Moreover, fragment-based drug design methods also will be employed to design novel and potent reversible selective Plk-2 inhibitors. The binding of several selective Plk-2 inhibitors to the target of Plk-2 will be determined by biophysics methods such as X-ray crystallography technique. One or few compounds gotten by these methods will be used to determine the phosphorylation of α-synuclein in rat brain upon oral administration and they represent useful probes for future studies of this therapeutic avenue toward the potential treatment of PD. This proposal will lay the foundation for developing effective drugs to cure PD.

帕金森氏症是一种严重威胁老年人健康的神经退行性疾病，目前尚无治愈药物。近来研究表明，Plk-2是α-突触核蛋白磷酸化的主要激酶，因而Plk-2是一个潜在的抗帕金森氏症的靶点。但到目前为止，Plk-2选择性抑制剂报道很少。本项目拟把本课题组前期得到的可逆Plk-2选择性抑制剂作为先导化合物，采用基于结构的药物设计方法设计和合成Plk-2选择性共价抑制剂以提高药效；在前期获得的Plk-2抑制剂优势分子片段基础上，运用X晶体衍射技术阐明它们与Plk-2蛋白的作用模式，采用基于片段的设计方法组装和合成新的高效可逆/不可逆Plk-2选择性抑制剂并评价它们在大鼠脑中降低α-突触核蛋白磷酸化效果，确证Plk-2抑制剂在α-突触核蛋白磷酸化过程的作用机理和帕金森氏症的治疗效果。本项目将为进一步开发安全有效的治疗帕金森氏症的新型靶向药物提供有益的线索。

帕金森氏症是一种严重威胁老年人健康的神经退行性疾病，目前尚无治愈药物。近来研究表明，Plk-2是α-突触核蛋白磷酸化的主要激酶，因而Plk-2是一个潜在的抗帕金森氏症的靶点。但到目前为止，Plk-2选择性抑制剂报道很少。本项目拟把本课题组前期得到的可逆Plk-2选择性抑制剂作为先导化合物，采用基于结构的药物设计方法设计和合成Plk-2选择性共价抑制剂以提高药效；在前期获得的Plk-2抑制剂优势分子片段基础上，运用X晶体衍射技术阐明它们与Plk-2蛋白的作用模式，采用基于片段的设计方法组装和合成新的高效可逆/不可逆Plk-2选择性抑制剂并评价它们在大鼠脑中降低α-突触核蛋白磷酸化效果，确证Plk-2抑制剂在α-突触核蛋白磷酸化过程的作用机理和帕金森氏症的治疗效果。本项目已经得到了多个新颖骨架的Plk2及Plk1抑制剂，如((tetrahydropteridin-2-yl)amino)benzenesulfonamide和(tetrahydropteridin-2-yl)1H-indole骨架，已对它们完成了初步的生物学评价，进一步的临床前研究正在进行中。发表论文14篇，申请专利5项。本项目将为进一步开发安全有效的治疗帕金森氏症的新型靶向药物提供有益的线索。