Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
Peptides International, Louisville, KY 40299, USA.
Sci Rep. 2017 Jan 3;7:39662. doi: 10.1038/srep39662.
Pain places a devastating burden on patients and society and current pain therapeutics exhibit limitations in efficacy, unwanted side effects and the potential for drug abuse and diversion. Although genetic evidence has clearly demonstrated that the voltage-gated sodium channel, Nav1.7, is critical to pain sensation in mammals, pharmacological inhibitors of Nav1.7 have not yet fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects. Using the tarantula venom-peptide ProTX-II as a scaffold, we engineered a library of over 1500 venom-derived peptides and identified JNJ63955918 as a potent, highly selective, closed-state Nav1.7 blocking peptide. Here we show that JNJ63955918 induces a pharmacological insensitivity to pain that closely recapitulates key features of the Nav1.7-null phenotype seen in mice and humans. Our findings demonstrate that a high degree of selectivity, coupled with a closed-state dependent mechanism of action is required for strong efficacy and indicate that peptides such as JNJ63955918 and other suitably optimized Nav1.7 inhibitors may represent viable non-opioid alternatives for the pharmacological treatment of severe pain.
疼痛给患者和社会带来了毁灭性的负担，而目前的疼痛治疗方法在疗效、不良反应以及药物滥用和滥用的可能性方面存在局限性。尽管遗传证据清楚地表明，电压门控钠离子通道 Nav1.7 对哺乳动物的疼痛感知至关重要，但 Nav1.7 的药理学抑制剂尚未完全再现 Nav1.7 缺失个体中观察到的剧烈镇痛作用。我们使用狼蛛毒液肽 ProTX-II 作为支架，设计了一个超过 1500 种毒液衍生肽的文库，并鉴定出 JNJ63955918 是一种有效的、高度选择性的、闭态 Nav1.7 阻断肽。在这里，我们表明 JNJ63955918 诱导对疼痛的药理学不敏感性，这种不敏感性与在小鼠和人类中观察到的 Nav1.7 缺失表型的关键特征非常相似。我们的研究结果表明，高度的选择性，加上依赖于闭态的作用机制，是实现强大疗效所必需的，并表明像 JNJ63955918 这样的肽和其他适当优化的 Nav1.7 抑制剂可能是治疗严重疼痛的可行非阿片类替代药物。
