钙调磷酸酶（Calcineurin, CN）是目前发现的唯一受Ca2+/CaM（Calmodulin）调节的蛋白磷酸酶，它由催化亚基CNA和调节亚基CNB组成。CN在机体内参与了许多重要的生理机能活动，如免疫系统中一些免疫应答基因的转录调控过程，学习记忆、细胞凋亡等的调节。在免疫反应调节方面，CN因此常被人们用作靶酶筛选免疫抑制剂。本实验室前期通过以CN为靶酶的药物筛选分子模型，从JHH中筛选出了对CN有抑制作用的单体化合物YDHH。本实验室前期研究证明YDHH在体外对CN活性有明显的抑制作用，在体内对免疫活性也有明显的抑制效果且具有低毒性特点。但是YDHH对CN活性的抑制机理未深入研究，且其在体内的免疫抑制活性相比常用免疫抑制剂CsA不是很理想，虽然相比后者有低毒性优势。 本文首先介绍利用光谱学方法深入研究YDHH对CN活性的抑制机理，然后在药效学研究中尝试将YDHH做成一种合适的口服剂型，从而提高其在体内的免疫抑制效果。 利用光谱学方法，研究YDHH对CN的作用。实验结果表明，YDHH能够与CN 1:1较强结合，并且初步判断出YDHH在CN上的结合区域，并且结合时YDHH对CN的二级结构能够产生影响。最后我们期望辅助分子模拟的手段，更加准确的了解YDHH与CN的结合结合时的结合位点。 通过小鼠迟发超敏反应实验和小鼠关节炎模型研究YDHH口服剂型的免疫抑制效果。实验结果表明，YDHH用少量无水乙醇完全溶解后再加入玉米油形成的乳化剂，作为口服剂型给药在体内动物实验中表现出了良好的免疫抑制效果。这使YDHH开发成为一种新型的免疫抑制药物又迈进了一步。

Calcineurin (CN), a unique Ca2+ and calmodulin-dependent protein serine/threonine phosphatase, contains two subunits: a catalytic A-subunit of 60 KD (CNA), and a regulatory B-subunit of 19 KD (CNB). Calcineurin participates in the regulation of many important physiological functions like the activation of T cell, the expression of IL-2, study, memory and the cell apoptosis. So CN was usually used as the target enzyme to screening the immunosuppressant in researching the immunoregulation. A molecular model with CN as the target enzyme for screening immunosuppressants had been established and finally a small molecular compound YDHH from JHH was founded. In our previous work, YDHH was preliminarily proved to be an inhibitor of CN and has significant immunosuppressive effect with very low toxicity in in vivo study. However, the immunosuppressive effects and in-depth inhibition mechanism of YDHH remained unclear. Also its immunosuppressive effect is not better than CsA, a normally used immunosuppressant, in in vivo excepting the only advantage of the low toxicity. In this study, we researched the inhibition mechanism of YDHH to CN using spectroscopy methods. And we also tried to determine a good oral dosage form of YDHH with a better immunosuppressive effect in in vivo. We studied the interaction between YDHH and CN by spectroscopy methods. The results showed us that YDHH can strongly binding to CN with the ratio of 1:1. The binding domain has probably been supposed. It is regretful that the docking between YDHH and CN , which could give us the more detail information about the binding of YDHH to CN, has not been finished due to the time limit. Also we studied the immunosuppressive effect of YDHH in oral dosage form by mouse model of Delayed type hypersensitivity (DTH) and Collagen-induced arthritis (CIA). An emulsified dosage was founded which has a much better immunosuppressive effect in animal experiments. It did a contribution to the YDHH using as a novel immunosuppressant in the future.