核苷类甲基转移酶抑制剂的研究进展  

Advances in nucleoside analogues as methyltransferase inhibitors

作　　者：张俊杰 刘同超 熊兵 ZHANG Jun-jie;LIU Tong-chao;XIONG Bing(Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China)

机构地区：[1]中国科学院上海药物研究所,上海201203 [2]中国科学院大学,北京100049

出　　处：《药学学报》2024年第5期1126-1150,共25页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82204187,82173658,81773572)。

摘　　要：S-腺苷-L-蛋氨酸(SAM)作为仅次于ATP第二普遍存在的辅助因子,其主要的功能是作为SAM依赖性甲基转移酶的甲基供体,对DNA、RNA、蛋白质等基本生命物质进行甲基化修饰。此过程构成了表观遗传调控、细胞信号转导和生物代谢循环的重要一环,参与多种疾病的发生与发展,因此,SAM依赖性甲基转移酶已成为药物研发的潜在靶点。最近,许多核苷类分子已经被开发为甲基转移酶的SAM竞争性抑制剂,从而阻断下游的信号通路,达到治疗相关疾病的目的。本文系统性回顾基于SAM结构开展改造的甲基转移酶抑制剂设计策略和研发过程,分析核苷类甲基转移酶抑制剂研发的不足和解决方法,为未来设计靶向甲基转移酶SAM结合位点的核苷类分子提供更多的思路。As the second largest cofactor after ATP in body,S-adenosyl-L-methionine(SAM)is responsible for methyl donor in SAM-dependent methyltransferases(MTases).The methylation of essential ingredients(e.g.,DNA,RNA,protein)plays a critical role in epigenetic regulation,cellular signal transduction and metabolic cycles,which is closely related to different kinds of diseases.Therefore,SAM-dependent methyltransferases are considered as promising drug targets.Currently,a growing number of nucleoside analogues have been developed as SAM-competitive inhibitors,blocking the downstream signaling pathways to cure diseases.In the review,we outline the design strategy and optimization process of methyltransferase inhibitors,analyze the shortcomings and solutions of developing nucleoside derivatives as MTase inhibitors,to provide guidance and broad direction to the development of nucleoside MTase inhibitors.

关 键 词：表观遗传学 S-腺苷-L-蛋氨酸 甲基转移酶 核苷类似物 

分 类 号：R914[医药卫生—药物化学]