化学修饰的环孢菌素类非免疫抑制性亲环素抑制剂进展  

Nonimmunosuppressive Cyclophilin Inhibitors Derived from the Cyclosporin Scaffolds

作　　者：姚贵阳[1] 房丽晶[1] 潘正银[1] 王恒山[2] 粟武[1] 

机构地区：[1]中国科学院深圳先进技术研究院,深圳518055 [2]广西师范大学化学与药学学院,桂林541000

出　　处：《集成技术》2015年第4期28-44,共17页Journal of Integration Technology

基　　金：深圳市引进海外高层次人才"孔雀计划"(KQCX20130628112914285);国家自然科学基金(21432003)

摘　　要：亲环素(Cyps)是一类在自然界分布广泛、具有高度保守性的多功能蛋白家族,也是重要的免疫抑制药物环孢菌素A(Cs A)的蛋白受体,具有肽基脯氨酰顺反异构酶(PPIase)活性。非免疫抑制性亲环素抑制剂是基于Cs A骨架而改造得到的衍生物,这些衍生物能够在抑制亲环素活性的同时降低免疫抑制活性。一些非免疫抑制性亲环素抑制剂(Alisporivir、SCY-635和NIM811)已经证明对丙型肝炎传染病治疗有临床疗效。最近的研究发现亲环素蛋白抑制剂还具有治疗多种病毒性感染,炎性症状,以及癌症的潜力。文章综述了非免疫抑制性环孢菌素衍生物在临床和临床前开发的构效关系,并讨论了这些候选药物的药代动力学和化学生物学特性。Cyclophilins（Cyps） are crucial to protein folding because that the ubiquitous proteins affect the cis-trans isomerization of Pro amide bonds. The immunosuppressive natural product cyclosporine A inhibits the enzymatic activity of the cyclophilins. Chemical modifi cation of cyclosporine scaffolds has produced many analogues that inhibit cyclophilins in vitro but have reduced immunosuppressive properties. Three nonimmunosuppressive cyclophilin inhibitors（alisporivir, SCY-635, and NIM811） have demonstrated clinical effi cacy for the treatment of hepatitis C infection. Recent publications suggest that cyclophilin inhibitors may have utility for the treatment of diverse viral infections, infl ammatory indications, and cancer. In this review, we document the structure-activity relationships of the nonimmunosuppressive cyclosporins in clinical and preclinical development. Aspects of the pharmacokinetic behavior and chemical biology of these drug candidates are also described.

关 键 词：亲环素 环孢菌素A 非免疫抑制 抗病毒 构效关系 

分 类 号：R96[医药卫生—药理学]