一系列新型同形及杂合糖簇的合成及DC-SIGN结合活性研究

doi:10.5246/jcps.2021.11.074

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (11): 859-873.DOI: 10.5246/jcps.2021.11.074

• 【研究论文】 • 下一篇

一系列新型同形及杂合糖簇的合成及DC-SIGN结合活性研究

蔡雪妮¹, 富戈¹, Martin Lepšík², Emanuele Paci³, 郭媛⁴^,^*(), 李中军¹^,^*(), 李庆¹^,^*()

1. 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
2. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 16610 Prague 6, Czech Republic
3. School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
4. School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK

收稿日期:2021-04-18 修回日期:2021-05-09 接受日期:2021-08-25 出版日期:2021-11-28 发布日期:2021-11-28
通讯作者: 郭媛, 李中军, 李庆
作者简介:
+ Tel.: +86-10-82805939, E-mail: zjli@bjmu.edu.cn
+ E-mail: qli@bjmu.edu.cn
+ E-mail: y.guo@leeds.ac.uk
基金资助:
National Natural Science Foundation of China (NSFC, Grant No. 21172015); Wellcome Trust (UK, Grant No. 097354/Z/11/Z); ML acknowledges the Research Project RVO: 61388963 of the Institute of Organic Chemistry and Biochemistry; Academy of Sciences of the Czech Republic, and the Czech Science Foundation (Grant No. P208/12/G016).

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

Xueni Cai¹, Ge Fu¹, Martin Lepšík², Emanuele Paci³, Yuan Guo⁴^,^*(), Zhongjun Li¹^,^*(), Qing Li¹^,^*()

1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 16610 Prague 6, Czech Republic
3 School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
4 School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK

Received:2021-04-18 Revised:2021-05-09 Accepted:2021-08-25 Online:2021-11-28 Published:2021-11-28
Contact: Yuan Guo, Zhongjun Li, Qing Li

摘要/Abstract

摘要：

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 (K_D = 2.6 μM)。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: 合成, 杂合糖簇, DC-SIGN, 结合活性, 对接

Abstract:

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 17b showed high DC-SIGN-binding activity (K_D = 2.6 μM). The structural determinants of this high affinity of 17b were rationalized by docking and compared with its much less potent isomer 17a. Therefore, 17b might serve as a base for the development of potent inhibitors of DC-SIGN-dependent viral infection.

Key words: Synthesis, Heteroglycoclusters, DC-SIGN, Binging-activity, Docking

Supporting:

蔡雪妮, 富戈, Martin Lepšík, Emanuele Paci, 郭媛, 李中军, 李庆. 一系列新型同形及杂合糖簇的合成及DC-SIGN结合活性研究[J]. 中国药学(英文版), 2021, 30(11): 859-873.

Xueni Cai, Ge Fu, Martin Lepšík, Emanuele Paci, Yuan Guo, Zhongjun Li, Qing Li. Synthesis of a series of novel homo- and hetero-glycoclusters and their binding activities to DC-SIGN[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(11): 859-873.

图/表 5

Figure 1. Structures of building blocks.

Scheme 1. Synthesis of compounds 2, 3, 6 and 7. Reagents and conditions: (a) NIS, TfOH, DCM, –20 °C, 1 h, 60% or 62% for 2 or 6, 36% or 30% for 3 or 7 respectively.

Scheme 2. Synthesis of glycoclusters 9, 11, 13a, 13b, 15a, 15b, 17a and 17b. Reagents and conditions: (b) CuI, DIPEA, toluence, R.T. (24 h); (c) CuSO4?5H2O, Na ascorbate, THF?H2O (1:1, v/v), 55 °C (6 h), R.T. (18 h); (d) MeONa, MeOH, R.T. (24 h); (e) Pd/C, H2, MeOH?EA (1:1, v/v), R.T. (24 h).

Figure 2. SPR steady-state analysis and binding response curves between immobilized DC-SIGN and injected 17b.

Figure 3. Comparison of the crystal structure of DC-SIGN CRD with GlcNAc-Man-Man-Man-GlcNAc pentasaccharide (PDB code 1K9I)[13] and modeled structure with ligands 17b and 17a. A, B and C are detailed structural Ca2+ coordination by ligands: bidentate coordination by O3 and O4 oxygens of GlcNAc-Man-Man-Man-GlcNAc as observed in the crystal structure (A), potential bidentate coordination by O3 and O2 oxygens of 17b (B), and strictly monodentate coordination by O2 oxygen of 17a (C) as obtained by docking (this work). D, E and F are the co-crystal structure of DC-SIGN CRD with GlcNAc-Man-Man-Man-GlcNAc[13] (D), and modeled structure of CRD complexed with 17b (E) or 17a (F). Colour coding: red-oxygen and green sphere-Ca2+. Hydrogen bonds are dotted. Figure rendered with PyMol[35]. In summary, docking of 17b and 17a suggested that the former compound was a potent binder of DC-SIGN because it effectively mimicked the binding of the GlcNAc-Man-Man-Man-GlcNAc pentasaccharide, in which it placed its three sugar units in analogous positions, including possible bidentate coordination of Ca2+ in the primary site.

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一系列新型同形及杂合糖簇的合成及DC-SIGN结合活性研究

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

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