Synthesis of a series of novel homo-and hetero-glycoclusters and their binding activities to DC-SIGN  

一系列新型同形及杂合糖簇的合成及DC-SIGN结合活性研究

作　　者：Xueni Cai Ge Fu Martin Lepsik Emanuele Paci Yuan Guo Zhongjun Li Qing Li 蔡雪妮;富戈;Martin Lepsik;Emanuele Paci;郭媛;李中军;李庆(北京大学药学院天然药物及仿生药物国家重点实验室,北京100191;Institute of Organic Chemistry and Biochemistry,Academy of Sciences of the Czech Republic,v.v.i.,Flemingovo nam.2,16610 Prague 6,Czech Republic;School of Molecular and Cellular Biology,Faculty of Biological Sciences,University of Leeds,Leeds,LS29JT,UK;School of Chemistry,University of Leeds,Leeds,LS29JK,UK)

机构地区：[1]State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University Health Science Center,Beijing 10019,China [2]Institute of Organic Chemistry and Biochemistry,Academy of Sciences of the Czech Republic,v.v.i.,Flemingovo nam.2,16610 Prague 6,Czech Republic [3]School of Molecular and Cellular Biology,Faculty of Biological Sciences,University of Leeds,Leeds,LS29JT,UK [4]School of Chemistry,University of Leeds,Leeds,LS29JK,UK

出　　处：《Journal of Chinese Pharmaceutical Sciences》2021年第11期859-873,共15页中国药学（英文版）

基　　金：National Natural Science Foundation of China(NSFC,Grant No.21172015);Wellcome Trust (UK,Grant No.097354/Z/11/Z);ML acknowledges the Research Project RVO61388963 of the Institute of Organic Chemistry and Biochemistry;Academy of Sciences of the Czech Republic,the Czech Science Foundation (Grant No.P20 8/12/G016)。

摘　　要：As a dendritic cell-specific C-type lectin receptor, DC-SIGN plays an important role in the early stages of many viral infections, including HIV and Ebola, making it an interesting therapeutic target. It has been found that DC-SIGN can recognize both highly mannosylated and branched fucosylated oligosaccharides. Herein, we synthesized a new series of homo-and Man-Fuc heteroglycoclusters with diverse structures. The binding properties of these compounds to tetrameric extracellular DC-SIGN were assessed by surface plasmon resonance(SPR). Heteroglycocluster 17 b showed high DC-SIGN-binding activity(K;= 2.6 μM). The structural determinants of this high affinity of 17 b were rationalized by docking and compared with its much less potent isomer 17 a. Therefore, 17 b might serve as a base for the development of potent inhibitors of DC-SIGN-dependent viral infection.DC-SIGN是星形细胞特异性C-型凝集素受体,在诸如HIV,Ebola等多种病毒早期感染阶段起着重要作用,因而可能成为有价值的治疗靶标。研究发现,DC-SIGN可以识别高甘露糖结构以及含有岩藻糖分支的寡糖。据此,合成了一系列新型的具有结构多样性的同形及甘露糖-岩藻糖杂合糖簇,并采用表面等离子共振技术(SPR)对此类化合物进行了DC-SIGN胞外结构域四聚体的结合活性测试。结果表明,杂合糖簇17b显示了较高的DC-SIGN结合活性(KD=2.6μM)。采用分子对接的方法,以低活性的异构体17a为对照,对17b的活性进行了结构因素方面的评价与解释。17b可能作为基础用于研发DC-SIGN依赖的病毒感染抑制剂。

关 键 词：Synthesis Heteroglycoclusters DC-SIGN Binging-activity DOCKING 

分 类 号：R916[医药卫生—药学]