基质金属蛋白酶抑制剂的研究进展

Progress in development of matrix metalloproteinase inhibitors

基质金属蛋白酶(MMPs)是一类钙离子和锌离子依赖的内肽酶,它们介导细胞外基质(ECM)的降解和组织重塑,促进肿瘤的侵袭和转移,调节宿主防御反应及正常的细胞功能。MMP抑制剂(MMPIs)可用于治疗肿瘤、骨关节炎及类风湿关节炎等疾病。近来发展了许多不同类别的抑制剂,但都未通过临床试验,故需采用不同的锌离子结合基(ZBG)设计具有选择性的抑制剂。本文概括了MMPs的三维结构,MMPIs的现状,小分子质量MMPIs的设计。综述了各类抑制剂的结构特点、治疗用途及已进入人类临床试验的化合物。

Matrix metalloproteinases （MMPs） belong to a family of calcium and zincions dependent proteinases involved in the degradation and remodeling of extracellular matrix proteins that are associated with the tumorigenic process. MMPs promote tumor invasion and metastasis, regulating host defense mechanisms and normal cell function.Thus, MMP inhibitors （MMPIs） are expected to be useful for the treatment of cancer, osteoarthritis, and rheumatoid arthritis. A vast number of MMPIs have been developed in recent years; following the failure of these inhibitors in clinical trials, more efforts have been directed to the design of specific inhibitors with different Zn-binding groups for selective usage. This review summarizes the current status of MMPIs, the design of small molecular weight MMPIs, a brief description of available three-dimensional MMP characteristic structures, clinical application of MMPIs, and the already entering clinical trial compounds in humans.