新型C型凝集素Dectin-1小分子配体的发现、优化与抗炎活性研究

Dectin-1 is a new type of C-type lectin, which is widely expressed on the surface of mononuclear/macrophage, dendritic cells and natural killer cells. Dectin-1 can recognize β-Glucan on the surface of fungi, initiate intracellular signaling pathway, and play an important role in antifungal immunity. Activated Dectin-1 mediates the secretion of various inflammatory factors, such as TNF-a, IL-6 and so on. It is of great significance in regulating immune and inflammation of the body. Overactivated Dectin-1 can induce autoimmune arthritis, uveal retinitis, enteritis, liver fibrosis, allergic pneumonia, peritonitis and other diseases. Dectin-1 is a new target for anti-inflammatory drugs, but there are no small molecular ligands at present. According to the hypothesis proposed by our laboratory, the Dectin-1 reverse agonist, LS-23, which has significant anti-inflammatory activity, was first discovered in our previous work. This project plan to take LS-23 as the lead compound, optimize the structure based on the X-ray crystal structure of Dectin-1 and β-glucan, and docking results with LS-23. After synthesis and assays of ~100 compounds, a drug candidate was expected to develop for the treatment of inflammation caused by excessive inflammatory factors, which may benefit for the development of a first-in-class drug.

Dectin-1是单核/巨噬细胞、树突细胞、自然杀伤细胞表面广泛表达的新型C型凝集素，能识别真菌表面的β-葡聚糖，启动胞内信号通路，在抗真菌免疫中发挥重要作用。Dectin-1活化后介导TNF-α、IL-6等多种炎性因子的分泌，在调节机体免疫、炎症方面具有重要的意义。Dectin-1的过度活化能诱导自身免疫性关节炎、葡萄膜视网膜炎，肠炎、肝纤维化、过敏性肺炎、腹膜炎等多种疾病。Dectin-1是抗炎药物的新靶点，但目前尚无小分子配体报道。根据本实验室提出的假说，在前期工作中首次发现了具有显著抗炎活性的Dectin-1反相激动剂LS-23。项目计划以LS-23为先导化合物，根据Dectin-1蛋白与β-葡聚糖的晶体结构及与LS-23的分子对接结果进行结构优化，完成约100个化合物的合成及活性筛选，期望开发出治疗过量炎症因子引起的炎症的候选药物，为下一步开发出首创新药奠定基础。

Dectin-1是单核/巨噬细胞、树突细胞、自然杀伤细胞表面广泛表达的新型C-型凝集素，能识别真菌表面的β-葡聚糖，启动胞内信号通路，在抗真菌免疫中发挥重要作用。Dectin-1活化后介导TNF-a、IL-6等多种炎性因子的分泌，在调节机体免疫、炎症方面具有重要的意义。但Dectin-1的过度活化诱导自身免疫性关节炎、葡萄膜视网膜炎，肠炎、肝纤维化、过敏性肺炎、腹膜炎等多种疾病。Dectin-1是抗炎药物的潜在靶点，本课题基于在前期工作中首次发现的具有显著抗炎活性的Dectin-1抑制剂，根据Dectin-1蛋白与β-葡聚糖的晶体结构以及与LS-23的分子对接结果进行结构优化，多批次完成了近百个化合物的合成及SPR、细胞水平的抗炎活性测试，从中发现了十几个化合物具有优良抗炎活性。剔除细胞毒化合物后，开展了作用机制研究，通过生物素偶联物发现该类化合物作用于细胞膜上的dectin-1受体，通过下调p-Syk，继而下调CARD9抑制炎症转录因子AP-1进入细胞核发挥抗炎作用；还可以下调程序性坏死关键蛋白p-RIPK1/RIPK3\MLKL，与程序性坏死信号通路发生交互，发挥抑制细胞程序性坏死作用。从本课题工作中优选出了两个化合物，开展了体内抗腹膜炎、急性炎症等药效试验，发现优选化合物安全性良好，在5~15mg/kg剂量下具有显著下调血清及脑组织中TNF-a、 IL-6等炎症因子作用，说明优选化合物在体内具有显著的抗炎作用，并对中枢神经具有显著保护作用。本课题完成了Dectin-1受体抑制剂的结构优化，初步优选出了候选药物，将来有望应用于TNF-a等炎症因子过量引起的疾病。.最近有研究发现入核蛋白Importin a3在神经性疼痛中发挥着重要作用，根据蛋白质组学结果，发现候选药物可以下调这一靶蛋白，并对小鼠骨癌痛具有优异的抑制作用，有望开发为无成瘾性的抗炎、镇痛药物。.

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