Novel analgesics based on antagonism of TRPV1-AKAP79 binding

疼痛是一个重要的临床问题，因为所有现有的镇痛药都有很大的副作用，而且对许多临床重要类型的疼痛效果也很差。膜离子通道TRPV1被热激活，对疼痛至关重要，因为当组织受损时，炎症介质降低TRPV1的温度阈值，使其即使在正常体温下也能被激活，从而引起持续的疼痛。我们已经发现了如何防止炎症介质对TRPV1的影响。脚手架蛋白AKAP79形成一个“篮子”结构，紧靠trpv1（负责降低其阈值的酶）。我们已经确定了结合位点，并可以使用竞争肽阻止结合。这些肽在小鼠疼痛模型中具有良好的镇痛作用，包括糖尿病神经病变模型，这是一种难治性的人类疼痛状况。我们将开发改良的TRPV1-AKAP79阻断肽，作为治疗顽固性疼痛的更好的镇痛药。

Pain is a significant clinical problem, because all existing analgesics have major side effects and are also poorly effective in many clinically important types of pain. A membrane ion channel, TRPV1, which is activated by heat, is critical for pain because when tissues are damaged, inflammatory mediators lower the temperature threshold of TRPV1 so that it can be activated even by normal body heat and thus cause ongoing pain. We have discovered how to prevent the effects of inflammatory mediators on TRPV1. A scaffolding protein, AKAP79, forms a "basket" structure which holds close to TRPV1the enzymes responsible for lowering its threshold. We have identified the binding site and can prevent binding using competitor peptides. These peptides give good analgesia in a mouse models of pain, including in a model of diabetic neuropathy, an intractable human pain condition. We will develop improved TRPV1-AKAP79 blocking peptides as better analgesics for intractable forms of pain.