Sophia Therapeutics LLC, 351 West 10th Street, Indianapolis, IN 46202, USA.
Neurosci Lett. 2013 Dec 17;557 Pt A(0 0):27-36. doi: 10.1016/j.neulet.2013.06.057. Epub 2013 Jul 3.
Chronic neuropathic pain management is a worldwide concern. Pharmaceutical companies globally have historically targeted ion channels as the therapeutic catechism with many blockbuster successes. Remarkably, no new pain therapeutic has been approved by European or American regulatory agencies over the last decade. This article will provide an overview of an alternative approach to ion channel drug discovery: targeting regulators of ion channels, specifically focusing on voltage-gated calcium channels. We will highlight the discovery of an anti-nociceptive peptide derived from a novel calcium channel interacting partner - the collapsin response mediator protein 2 (CRMP2). In vivo administration of this peptide reduces pain behavior in a number of models of neuropathic pain without affecting sympathetic-associated cardiovascular activity, memory retrieval, sensorimotor function, or depression. A CRMP2-derived peptide analgesic, with restricted access to the CNS, represents a completely novel approach to the treatment of severe pain with an improved safety profile. As peptides now represent one of the fastest growing classes of new drugs, it is expected that peptide targeting of protein interactions within the calcium channel complex may be a paradigm shift in ion channel drug discovery.
慢性神经性疼痛管理是一个全球性的关注点。全球制药公司历史上一直将离子通道作为治疗学的核心，取得了许多重大成功。值得注意的是，在过去十年中，没有任何新的疼痛治疗药物获得欧美监管机构的批准。本文将概述一种离子通道药物发现的替代方法：靶向离子通道调节剂，特别是针对电压门控钙通道。我们将重点介绍一种新型钙通道相互作用伙伴—— collapsin 反应介导蛋白 2（CRMP2）衍生的抗伤害性肽的发现。该肽在多种神经性疼痛模型中的体内给药可减轻疼痛行为，而不影响交感相关心血管活动、记忆检索、感觉运动功能或抑郁。一种 CRMP2 衍生的肽类镇痛药，其进入中枢神经系统的途径受限，为治疗严重疼痛提供了一种全新的方法，且具有改善的安全性。由于肽类目前是增长最快的新药类别之一，预计钙通道复合物内蛋白相互作用的肽靶向可能是离子通道药物发现的范式转变。
