作用钾通道Kv1.3免疫抑制多肽药物的发现、功能与优化

The autoimmune diseases are the third largest diseases of leading death and disability. Although the first immImmunosuppressive peptide ShK-186 targeting Kv1.3 channels in the lymphocyte entered into the clinical trial, their low selectivity and side-effect due to interactions with other human potassium channels are the key scientific question seriously affecting peptide drug research and development. Based on the 20-year’s achievements, functional studies of many candidate immImmunosuppressive peptides and the breakthrough of new drug target in Kv1.3 channel (J Biol Chem, 2015, 290: 15487; FASEB J, 2015,29: 4324), this project will focus the key scientific question on the structural basis of selectivity of immImmunosuppressive peptides targeting Kv1.3 channel, in depth carry out researches on the selectivity indentification, optimization and function of the first generation of immImmunosuppressive peptide drugs acting on the classical target of Kv1.3 channel, and innovatively carry out researches on the screening, optimization and function of the second generation of immImmunosuppressive peptide drugs acting on the novel target of Kv1.3 channel. These work will obtain many both high affinity and selectivity immImmunosuppressive peptide drug leads with intellectual property rights, and elucidate their structure-function relationships and interaction mechanisms, which lay the scientific foundation of immImmunosuppressive peptide drugs in the field of application and development.

自身免疫性疾病是第3大致死致残的疾病。尽管第一个靶向钾通道Kv1.3免疫抑制多肽ShK-186已进入临床试验，但解决多肽药物临床应用的关键问题仍是提高药物选择性和降低药物毒副作用。基于团队20余年多肽研究工作积累、系列较高选择性免疫抑制多肽的结构功能研究和钾通道Kv1.3新靶点的重大发现（J Biol Chem, 2015, 290: 15487; FASEB J, 2015, 29: 4324），本项目围绕“作用钾通道Kv1.3免疫抑制多肽选择性的结构基础”关键科学问题，系统深入开展作用钾通道Kv1.3经典靶点的第1类免疫抑制多肽药物的选择性鉴定、功能评价和结构优化研究，创新开展作用钾通道Kv1.3新靶点的第2类免疫抑制多肽药物的筛选、功能评价和结构优化研究，以获得系列高活性和高选择性的免疫抑制多肽先导药物，并阐明它们的构效关系及作用机制，奠定我国免疫抑制多肽药物应用开发的科学基础。

该项目针对作用钾通道Kv1.3孔区的第1类免疫抑制多肽和跨膜螺旋S1-S2胞外Linker的第2类免疫抑制多肽开展药物发现、功能与优化研究，以发现高选择性免疫抑制多肽。在项目实施过程中，依据项目团队提出的“多肽作用钾通道的键合模式与多肽选择性的相关性”创新假设，发现了作用钾通道Kv1.3高选择性多肽BmKTX，在细胞和动物水平上开展了多肽BmKTX的药理学功能试验，取得了预期效果。在此基础上，利用“在90°C范围内小角度摆动多肽BmKTX的键合模式”优化新策略，结构优化获得了高选择性多肽ADIP-6和ADIP-6-K33H，在细胞和动物水平上取得了多肽ADIP-6药理学功能试验的预期效果。利用“在360°C范围内小角度旋转多肽BmKTX的键合模式”优化新策略，结构优化获得了高选择性多肽ADIP-28。这些多肽药物研发工作为我国免疫抑制多肽药物应用开发奠定了科学基础。