Development and Biological Evaluation of Cytokine Macrophage-migration Inhibitor (MIF) Non-Steroidal antagonists

巨噬细胞移动抑制因子（MIF）在先天性和适应性免疫系统中具有广泛的促炎作用。CIA的实验室已经通过类风湿性关节炎（RA）模型的研究证明了MIF在慢性炎症病理学中的潜在重要性。与其他慢性炎症性疾病相似，MIF在人RA中过表达，并诱导RA细胞中关键病理过程的激活。此外，MIF与mAb的拮抗作用深刻地抑制了RA和其他炎性疾病的模型，证实了MIF作为人类炎性疾病的治疗靶点。MIF的X-射线晶体结构已被公布，推定的活性部位已被充分表征。我们已经推导出MIF的结构特征，揭示了主客体亲和力的结构互补性。这一信息已被用于合成新的化合物拮抗MIF。我们已经设计、合成并测试了几类化合物，这些化合物在新的内部体外生物测定中显示出从毫到纳米摩尔水平的活性。

The cytokine macrophage-migration inhibitory factor (MIF) has a broad range of pro-inflammatory effects in the innate and adaptive immune system. CIA’s lab has demonstrated the potential importance of MIF in the pathology of chronic inflammation via studies in models of rheumatoid arthritis (RA). Similarly to other chronic inflammatory diseases, MIF is overexpressed in human RA, and induces activation of key pathological processes in RA cells. Moreover, antagonism of MIF with mAb profoundly inhibits models of RA and other inflammatory diseases, confirming MIF as a therapeutic target in human inflammatory disease. The X-ray crystal structure of MIF has been published and the putative active site fully characterised. We have deduced structural features of MIF that reveal aspects of the structural complementarity of host-guest affinity. This information has been used in the synthesis of new compounds to antagonise MIF. We have designed, synthesised and tested several classes of compounds, which have shown activity from milli to nano-molar levels in novel in-house in vitro bioassays.