电压门控钠离子通道亚型1.8（Nav1.8）主要参与炎症性疼痛、神经性疼痛和对伤害性刺激反应的信号传递，特异性阻断Nav1.8的化合物有望开发成新一类的镇痛药物。本项目前期从中国南海18种芋螺中克隆得到421种全新的芋螺多肽基因，并通过iCTX和分子对接模拟的方法预测得到可能作用于人Nav1.8的20种多肽。本项目拟通过固相化学合成的方法合成这20种芋螺多肽，利用膜片钳技术检测20种多肽对人8种钠离子通道亚型Nav1.1-Nav1.8作用（已完成1种多肽检测），筛选出特异性抑制人Nav1.8电流的多肽，并通过丙氨酸扫描、氨基酸的插入缺失和碱性氨基酸替代等方法改造多肽氨基酸序列，提高多肽抑制人Nav1.8活性，通过核磁共振解析多肽的空间结构，利用三种小鼠镇痛模型观察多肽治疗的疼痛类别及镇痛效果，通过细胞增殖、凋亡、大鼠行为学和脊髓组织病变检测多肽的神经毒性，为镇痛新药的研发奠定基础。

Voltage gated sodium channel subtype 1.8（Nav1.8）was mainly involved in inflammatory pain, neuropathic pain and transduction of nociceptive information. Compounds that specificly block Nav1.8 were expected to be developed into novel analgesic drugs. In our previous study, 421 novel conopeptide genes were identified from 18 Conus species, which inhabits South China Sea. 20 of the 421 conopeptides were speculated to have Nav1.8 activities by iCTX and molecular docking. In this study, in order to find Nav1.8 specific inhibitors, 20 conopeptides were synthesized by solid-phase peptide synthesis and the Nav1.1-1.8 activities were tested by patch clamp. Alanine-scanning, amino acid insertions and deletions and basic amino acid substitution were used to design conopeptide analogs, which were tested Nav1.8 activities to find more efficient analogs. NMR was used to study the structure of conopeptide. Three animal pain models were used to test the analgesic effects of conopeptide. Cell proliferation assay, cell apoptosis，rat behavioral observation and rat spinal cord tissue lesion were used to detect neurotoxicity of conopeptide. This study will provide analgesic drug candidates and ion channel probes.