靶向诱导蛋白降解作为药物开发新策略  被引量:4

Protein degradation as an innovative strategy in drug discovery

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作  者:尤启冬[1,2] 陆朦辰 姜正羽 

机构地区:[1]中国药科大学江苏省药物分子设计与成药性优化重点实验室,江苏南京210009 [2]中国药科大学药学院药物化学系,江苏南京210009

出  处:《药学学报》2017年第12期1777-1782,共6页Acta Pharmaceutica Sinica

基  金:国家自然科学基金资助项目(81230078;81602948)

摘  要:基于机制药物研发的核心问题是寻找和发现可靠的药物靶标。随着基因组学和蛋白质组学的理论及实验技术的快速发展,有不少非酶蛋白被确定为药物靶标。这些非酶蛋白类药物靶标难以用传统的、通过占据活性位点的调控方式来设计和发现疾病治疗药物。近年来,利用人体自身的泛素-蛋白酶体系统靶向诱导目的蛋白降解方法,可实现对众多非酶蛋白的有效抑制,成为创新药物研究的又一新的亮点。该方法通过设计靶向诱导蛋白降解的缀合物,该缀合物含有双功能单元分别识别和结合目的蛋白和泛素E3连接酶,诱导泛素化复合体组装,实现对特定的目的蛋白泛素化,最后诱导目的蛋白降解。这一创新的药物直接调控体内蛋白含量的策略极大拓展了潜在药物靶标的范围,为创新药物研究提供了广阔的新思路。The success rate of mechanism-based drug discovery depends on the drug targets.With the rapid development of genomics and proteomics,a lot of nonenzymic proteins have been identified as potential drug targets.However,these nonenzymic proteins cannot be regulated by occupying the active site,which were recognized as undruggable targets.Direct regulation of the concentration of these proteins in cells by the innate ubiquitin-proteasome is a potential approach to target these proteins.The ubiquitination of target protein by E3 ligase is the key step for ubiquitin-proteasome mediated protein degradation.Proteolysis targeting chimeras(PROTACs) can facilitate the assembly of complex that consists of the target protein and E3 ligase.The target protein will be ubiquitinated,leading to the degradation by proteasome.This type of regulation mechanism can expand the scope of potential drug targets,and the development of PROTACs may be an innovative strategy in drug discovery.

关 键 词:泛素E3连接酶 蛋白降解 靶向诱导蛋白降解缀合物 

分 类 号:R916[医药卫生—药学]

 

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