海绵中Syk抑制活性先导化合物的发现及其抗过敏作用机制

Allergic diseases are listed as one of the diseases that need to be studied and prevented in the 21st century. Spleen tyrosine kinase (Syk) is an important target for the treatment of allergic diseases. The applicant isolated six novel antiallergic compounds from two sponges Hippospongia lachne and Dysidea villosa. They inhibited the release of beta-hexosaminase more actively than ketotifen. And they effectively inhibit the production of inflammatory mediators IL-4 and LTB4. The antiallergic mechanism of the new compound dysivillosin A based on Syk/PLCγ1 signaling pathway was preliminarily clarified. This project intends to use RBL-2H3 cell degranulation and Syk inhibitory activity screening model to track and isolate active compounds by chromatographic separation technology and determine their planar and stereo structures, to explore their structure-activity relationship on the basis of systematically evaluating their anti-allergic and Syk inhibitory activities, and to elucidate the mechanisms of targeting inhibition of Syk by highly active compounds based on IgE/FcεRⅠ signaling pathway. 1-2 lead compounds with Syk inhibitors of antiallergic activity will be obtained. These findings will provide an important basis for the development of new marine antiallergic drugs.

过敏性疾病被列为21世纪需要重点研究和防治的疾病之一。脾酪氨酸激酶（Syk）是治疗过敏性疾病的重要靶标。申请人前期从两种海绵Hippospongia lachne和Dysidea villosa中发现了6个结构新颖的抗过敏活性化合物，它们抑制β-己糖胺酶释放的活性均强于阳性对照药酮替芬，能有效抑制炎性介质IL-4和LTB4生成，并初步阐明了新化合物dysivillosin A基于Syk/PLCγ1信号通路的抗过敏作用机制。本项目拟利用RBL-2H3细胞脱颗粒和Syk抑制活性筛选模型，结合色谱分离技术追踪分离活性化合物，确定其平面及立体结构；在系统评价化合物抗过敏和Syk抑制活性基础上，探究其构效关系；阐明强活性化合物基于IgE/FcεRⅠ信号通路靶向抑制Syk的作用机制。获得1-2个Syk抑制类抗过敏活性先导化合物，为开发新型海洋抗过敏药物提供重要依据。

海绵是海洋新天然产物的重要来源。本项目对5种海绵进行系统的化学成分和生物活性研究，共获得73个化合物，包括37个萜类化合物、10个倍半萜醌类化合物、4个长链脂肪族类化合物、7个甾醇类化合物、9个吡啶生物碱类化合物、4个聚酮类化合物、1个二萜糖苷类化合物、1个苯酚类化合物，其中新化合物38个。运用质谱和核磁共振等技术确定化合物的平面结构，综合利用改良Mosher法、NMR计算、DP4+和CP3概率分析、Snatzke法、ECD计算、X-ray单晶衍射等方法确定了新化合物的绝对构型。利用DNP-IgE诱导的RBL-2H3细胞脱颗粒模型，发现具有抗过敏活性化合物10个。另外测试了化合物的抗炎、细胞毒、抗菌等活性，获得具有细胞毒活性化合物2个，抗炎活性化合物6个。共发表基金标注SCI论文6篇，其中第一作者2篇，共同第一作者1篇。协助培养博士研究生1名，硕士研究生2名，均已顺利毕业并获得相应学位。通过本项目的实施，丰富了我国西沙海绵化学库和海洋抗过敏活性分子库，为进一步高效利用我国海洋生物资源提供了支持，为研究我国自主知识产权的创新药物奠定了物质基础。