天然小分子化合物乙酰基-11-羰基-β-乳香酸（AKBA）及修饰物在治疗银屑病中的蛋白靶点和构效机制

银屑病的治疗是困扰世界皮肤病领域的一大难题，患者数量多且需终生服药，加之临床急需有效的药物，因此市场潜力巨大。在对银屑病发病机理和治疗方法的研究中，申请人前期研究成果已以第一作者身份被《Journal of Immunology》于2015年3月2日接收发表。在此基础上，我们发现从天然植物乳香中提取的小分子化合物乙酰基-11-羰基-β-乳香酸（AKBA）具有通过抑制NF-κB通路缓解小鼠类银屑病表型，以及在体外抑制Th0向Th17分化的功能。本项目拟通过使用biotin标记的AKBA和其修饰物，采取pull down的方法钓取其直接作用靶蛋白，并以此为出发点阐明AKBA和其修饰物缓解小鼠类银屑病炎症表型的分子机制和信号通路。并通过结构生物学和X射线晶体技术解析靶蛋白晶体结构以及结合小分子化合物后蛋白结构变化，明晰构效关系，阐明化学修饰提高AKBA生物学活性的机理，推动此类小分子的临床转化。

The treatment of psoriasis is a major problem that troubles the field of skin disease therapy. The market of psoriasis medicine is huge for that there are so many patients and so few effective therapies as well as the medical need is always lifelong. During the study of pathogenesis and treatment of psoriasis, the applicant’s previous research achievements have been accepted and published as the first author by The Journal of Immunology on 2nd Mar, 2015. On this basis, we find that acetyl-11-carbonyl-β-boswellic acid (AKBA), a small molecule compound extracted from natural plant lactic acid, has the function of improving murine psoriasis phenotype by depressing NF-κB pathway and inhibiting the differentiation of Th0 to Th17. The project intends to use biotinylated AKBA and its modifications which were modified by our group to fish their direct targeting proteins using pull down strategy. By this means, we can elucidate the molecular mechanism and signal pathway of AKBA and its modifications in alleviating murine psoriasis phenotype. The project will then clear the structure-activity relationships between these small molecule compounds and protein targets by resolving the crystal structure of target protein and the structure changes of proteins after small molecules binding through proteomics and structural biology techniques, which will clarify the mechanism that chemical modification improved the biological activity of AKBA. This knowledge will promote the clinical transformation of these small molecule compounds.