抗病毒核苷酸类似物磷酸化修饰研究进展  

Research Progress in Phosphorylation Modification of Antiviral Nucleotide Analogs

作　　者：梁星星 王佳[1] 许文涛[1] LIANG Xing-xing;WANG Jia;XU Wen-tao(Department of Nutrition and Health,China Agricultural University,Beijing 100091;College of Food Science and Nutritional Engineering,China Agricultural University,Beijing 100083)

机构地区：[1]中国农业大学营养与健康系,北京100091 [2]中国农业大学食品科学与营养工程学院,北京100083

出　　处：《生物技术通报》2022年第2期218-226,共9页Biotechnology Bulletin

基　　金：中国农业大学“2115”人才培育发展支持计划。

摘　　要：核苷(酸)类似物是一类抗病毒前药,其进入人体细胞后经过逐步磷酸化生成核苷三磷酸类似物发挥抗代谢药作用,主要通过抑制病毒复制和促进侵染细胞凋亡,达到疾病治疗效果。其中,核苷类似物在细胞内经激酶活化的代谢转化过程通常是不充分的,导致最后生成的核苷三磷酸类似物浓度较低,降低了作用效果。因此,通过直接制备核苷酸类似物作为抗病毒前药,在磷酸基上修饰亲脂的、可裂解的基团,使其稳定性提高,细胞吸收摄取能力增强,可避开细胞内的磷酸化限速步骤,从而有效提高最终的活性核苷三磷酸浓度,发挥更好的抗病毒作用。总结了核苷酸类似物的发展过程,列举分析了不同类型核苷酸类似物的合成和修饰手段,以期为进一步发展高效安全的抗病毒核苷酸类似物提供良好借鉴。Nucleoside and nucleotide analogs are a class of antiviral prodrugs.After entering the human cells,they are gradually phosphorylated to generate nucleoside triphosphate analogues to serve as the antimetabolites.The resulted triphosphate analogues achieve the effect of disease treatment mainly by inhibiting virus replication and promoting apoptosis of infected cells.During the phosphorylation,the metabolic conversion process of nucleoside analogs activated by kinases in the cell is usually insufficient,resulting in a lower concentration of the final nucleoside triphosphate analogues,thus reducing the antiviral effect.Therefore,by directly preparing nucleotide analogs as antiviral prodrugs,the lipophilic and cleavable groups are modified on the phosphate groups to increase its stability and enhance the absorption capacity of cells,which can avoid the rate-limiting step of phosphorylation in the cell.In the end,it can effectively increase the final active nucleoside triphosphate concentration and exert a better antiviral effect.This article summarizes the development process of nucleotide analogs,and lists and analyzes the synthesis and modification methods of different types of nucleotide analogs,aiming to provide useful references for the further development of efficient and safe antiviral nucleotide analogs in the future.

关 键 词：核苷(酸)类似物 抗病毒前药 磷酸化修饰 稳定性 亲脂性 

分 类 号：TQ460.1[化学工程—制药化工]