Alkoxypsoralens, Small Molecule Blockers of the Voltage-Gated Kv1.3 Channel

烷氧基补骨脂素，电压门控 Kv1.3 通道的小分子阻断剂

• 批准号: 7141943
• 负责人: HEIKE WULFF
• 金额: $ 26.24万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141943
• 关键词: autoimmune disorder; bioengineering /biomedical engineering; cell mediated lymphocytolysis test; contact dermatitis; cytotoxic T lymphocyte; disease /disorder model; drug discovery /isolation; helper T lymphocyte; high performance liquid chromatography; immunosuppression; immunotoxicity; ion channel blocker; kidney transplantation; laboratory rat; longitudinal animal study; mass spectrometry; myasthenia gravis; nanotechnology; nonhuman therapy evaluation; pharmacokinetics; potassium channel; psoralens; psoriasis; small molecule; transplant rejection

DESCRIPTION (provided by applicant): Specific K+ channel modulation offers an enormous potential for the development of new drugs. 1 channel that constitutes an especially promising therapeutic target is the voltage-gated Kv1.3 channel. Homomeric Kv1.3 channels are found in T and B lymphocytes and their expression is up-regulated in terminally differentiated effecter memory T (TEM) cells and class-switched memory B cells suggesting that Kv1.3 blockers should be useful for the treatment of autoimmune diseases such as multiple sclerosis, type-1 diabetes, psoriasis, contact dermatitis, rheumatoid arthritis and myasthenia gravis. This concept has been validated by the demonstration that autoreactive T cells from patients with multiple sclerosis and type-1 diabetes are predominantly Kv1.3-high TEM cells and that the Kv1.3 blocking peptide ShK can treat an animal model of multiple sclerosis. However, despite Kv1.3's obvious therapeutic importance, the pharmaceutical industry has so far been unsuccessful in developing selective and potent small molecule Kv1.3 blockers. With the alkoxypsoralen PAP-1 my laboratory recently identified the first small molecule inhibitor of Kv1.3 that blocks the channel with an EC50 of 2 nM and displays selectivity over the cardiac potassium channel Kv1.5. PAP-1 does not exhibit cytotoxic or phototoxic effects, is negative in the Ames test, potently inhibits the proliferation of human TEM cells and suppresses delayed type hypersensitivity (DTH), a TEM cell mediated reaction, in rats when administered intraperitoneally or orally. PAP-1 therefore, seems to constitute an excellent new tool to further explore Kv1.3 as a target for immunosuppression and could potentially be developed into orally available immunomodulator. With the help of this proposal we intend to thoroughly explore the therapeutic potential of PAP-1. Under Aim-1, we will determine PAP-1's pharmacokinetics and test which effect long-term suppression of memory cells with PAP-1 has on the immune system. Under Aim 2, we will test whether PAP-1 treats allergic contact dermatitis, an animal model for CD8+ T cell mediated skin reactions like psoriasis, and experimental autoimmune myasthenia gravis, a model for the T-cell dependent antibody-mediated autoimmune disease myasthenia gravis. Since TEM cells also play an important role in early and late-stage transplant rejection, we will further test whether PAP-1 can suppress acute and chronic rejection in a rat kidney transplant model (Aim 3). Lay: Potassium channels are proteins that tunnel the cell membrane and conduct potassium ions. 1 of these channels, called Kv1.3, is expressed in white blood cells and has been proposed as a potential new therapeutic target for the treatment of autoimmune diseases. The aims of our proposal are to test a Kv1.3 blocker that we designed in animal models of autoimmune diseases and transplant rejection.

描述（由申请人提供）：特异性K+通道调节为新药开发提供了巨大的潜力。构成特别有希望的治疗靶点的Kv1.1通道是电压门控Kv1.3通道。在T和B淋巴细胞中发现了同源Kv1.3通道，并且它们的表达在终末分化的效应记忆T（TEM）细胞和类别转换记忆B细胞中上调，这表明Kv1.3阻断剂可用于治疗自身免疫性疾病，例如多发性硬化、1型糖尿病、银屑病、接触性皮炎、类风湿性关节炎和重症肌无力。这一概念已得到证实，证明多发性硬化症和1型糖尿病患者的自身反应性T细胞主要是Kv1.3高TEM细胞，Kv1.3阻断肽ShK可以治疗多发性硬化症的动物模型。然而，尽管Kv1.3具有明显的治疗重要性，但制药行业迄今为止在开发选择性和有效的小分子Kv1.3阻断剂方面并不成功。我的实验室最近发现了第一个Kv1.3的小分子抑制剂，其阻断通道的EC 50为2 nM，并显示出对心脏钾通道Kv1.5的选择性。PAP-1不显示细胞毒性或光毒性作用，在艾姆斯试验中为阴性，当腹膜内或口服给药时，在大鼠中有效地抑制人TEM细胞的增殖并抑制迟发型超敏反应（DTH）（一种TEM细胞介导的反应）。因此，PAP-1似乎构成了进一步探索Kv1.3作为免疫抑制靶点的极好的新工具，并且可能被开发成口服可用的免疫调节剂。在此提议的帮助下，我们打算彻底探索PAP-1的治疗潜力。在Aim-1中，我们将确定PAP-1的药代动力学，并测试PAP-1对记忆细胞的长期抑制对免疫系统的影响。在目标2下，我们将测试PAP-1是否治疗过敏性接触性皮炎（CD 8 + T细胞介导的皮肤反应如银屑病的动物模型）和实验性自身免疫性重症肌无力（T细胞依赖性抗体介导的自身免疫性疾病重症肌无力的模型）。由于TEM细胞在早期和晚期移植排斥反应中也发挥重要作用，我们将进一步测试PAP-1是否可以在大鼠肾移植模型中抑制急性和慢性排斥反应（目的3）。钾离子通道是一种蛋白质，它能穿透细胞膜并传导钾离子。这些通道中的1个，称为Kv 1.3，在白色血细胞中表达，并已被提出作为治疗自身免疫性疾病的潜在新治疗靶点。我们建议的目的是测试我们在自身免疫性疾病和移植排斥的动物模型中设计的Kv1.3阻断剂。