Department of Pharmacology, University of California Davis, Davis, CA, USA.
Saniona A/S, Ballerup, Denmark.
Nat Rev Drug Discov. 2019 May;18(5):339-357. doi: 10.1038/s41573-019-0013-8.
Ion channels play fundamental roles in both excitable and non-excitable tissues and therefore constitute attractive drug targets for myriad neurological, cardiovascular and metabolic diseases as well as for cancer and immunomodulation. However, achieving selectivity for specific ion channel subtypes with small-molecule drugs has been challenging, and there currently is a growing trend to target ion channels with biologics. One approach is to improve the pharmacokinetics of existing or novel venom-derived peptides. In parallel, after initial studies with polyclonal antibodies demonstrated the technical feasibility of inhibiting channel function with antibodies, multiple preclinical programmes are now using the full spectrum of available technologies to generate conventional monoclonal and engineered antibodies or nanobodies against extracellular loops of ion channels. After a summary of the current state of ion channel drug discovery, this Review discusses recent developments using the purinergic receptor channel P2X purinoceptor 7 (P2X7), the voltage-gated potassium channel K1.3 and the voltage-gated sodium channel Na1.7 as examples of targeting ion channels with biologics.
离子通道在兴奋和非兴奋组织中都发挥着重要作用，因此成为治疗多种神经、心血管和代谢疾病以及癌症和免疫调节的有吸引力的药物靶点。然而，用小分子药物实现对特定离子通道亚型的选择性一直具有挑战性，目前用生物制剂靶向离子通道的趋势日益增强。一种方法是改善现有或新型毒液衍生肽的药代动力学。与此同时，最初使用多克隆抗体的研究证明了用抗体抑制通道功能的技术可行性，现在有多个临床前项目正在利用各种可用技术的全部范围，针对离子通道的细胞外环生成传统的单克隆和工程化抗体或纳米抗体。在总结目前离子通道药物发现的现状后，本综述以嘌呤能受体通道 P2X 嘌呤受体 7（P2X7）、电压门控钾通道 K1.3 和电压门控钠通道 Na1.7 为例，讨论了用生物制剂靶向离子通道的最新进展。
