α4整合素与配体识别的分子机制及基于结构的小分子抑制剂设计

项目名称： α4整合素与配体识别的分子机制及基于结构的小分子抑制剂设计

项目编号： No.81501368

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 余雅梅

作者单位： 四川大学

项目金额： 18万元

中文摘要： α4整合素与配体MAdCAM-1、VCAM-1的相互识别在淋巴细胞的迁移、归巢，及炎症反应中发挥着重要作用。阻断α4整合素与配体相互作用的抗体（Natalizumab、Vedolizumab）已被批准上市，用于治疗多发性硬化症和肠炎。但抗体药物的多种局限性使得小分子药物的研发迫在眉睫。基于结构的计算机辅助药物设计将大大缩短药物研发周期， 减少研发成本。早期我们解析了整合素α4β7分别与Natalizumab、Vedolizumab、小分子抑制剂RO0505376的复合物晶体结构，阐明了它们的作用机理。本课题致力于解析整合素α4β1、 α4β1与VCAM-1复合物、 α4β7与MAdCAM-1复合物的晶体结构，在原子水平阐明α4整合素对配体的识别机制，并基于结构设计筛选出专一性强、亲和性高的小分子抑制剂，为α4整合素相关免疫疾病的治疗提供结构基础和治疗性小分子先导化合物。

中文关键词： α4整合素；；MAdCAM-1；；VCAM-1；蛋白质结构；药物设计

英文摘要： The interaction between α4 integrin and MAdCAM-1 or VCAM-1 plays an important role in lymphocyte migration and homing and inflammation. The α4 integrin antibodies, Natalizumab and Vedolizumab, have been approved for the treatment of multiple sclerosis and inflammation bowel disease. However, due to the shortcomings of antibodies compared to small-molecule drugs, it is urgent to develop small-molecule drugs against α4 integrins. Structure-based computer-aided drug design will greatly shorten the drug development cycle and reduce the cost of drug development. Previously, we have determined the crystal structures of α4β7 complexed either with Natalizumab or Vedolizumab or a small molecule antagonist RO0505376. Now, we are aiming to solve the crystal structures of α4β1, α4β7/MAdCAM-1 complex and α4β1/VCAM-1 complex. Then based on these structures, we will design a bunch of small molecules and screen out the high-affinity, high-specificity ones for α4β7 and α4β1, respectively. This study will help to understand the recognition between α4 integrin and its ligands and also help to develop new treatment of α4 integrin-related immune diseases.

英文关键词： α4 integrin; MAdCAM-1; VCAM-1;protein structure;drug design