Sequence controlled glycopolymers for selective lectin targeting

用于选择性凝集素靶向的序列控制糖聚合物

• 批准号: EP/P009018/1
• 负责人: Remzi Becer
• 金额: $ 12.8万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FP009018%2F1
• 关键词: Sequence; controlled; glycopolymers; selective; lectin

Carbohydrate binding proteins (CBPs) mediate diverse biological functions such as endocytosis, host-pathogen interactions, cell adhesion & trafficking and intracellular signal transduction. Exact chemical structures of some glycoproteins have already been reported in the literature. However, the chemical synthesis of even a small section of glycoprotein structures are extremely challenging and still may not exhibit the same biological activity in comparison to when they are incorporated into highly sophisticated complete glycoprotein structures. Glycopolymers (GP) have been shown to mimic glycan functions due to their multivalency and ability to bind various CBPs, but they lack CBP specificity. Thus development of systematic GP libraries with precise sequence control, architecture and folding in order to identify their specific binding to human dendritic cell (DC) carbohydrate binding proteins is highly appealing. Highly efficient chemical routes to prepare precision GPs while increasing the diversity in coding by altering carbohydrate type and number per polymer chain, microstructural distribution along the chain, and architecture of the chain will be investigated. Each of these parameters are known to have an enormous effect on specific recognition, binding kinetics and DC signalling. Sugar code in a human body is a highly complex and well established mechanism, which is responsible of various biological recognition events. The specific recognition of carbohydrate binding proteins on immune system related cells have a critical importance for improved health of humans. This project is concerned with developing a series of synthetic carbohydrate containing macromolecules that can target specific carbohydrate binding proteins on dendritic cells. The development of such a synthetic sugar code would potentially open the doors of precisely specific cell targeted drug delivery to selected cells. Moreover, such glyco structures would induce cell signalling upon interaction with certain lectins that may activate cell proliferation or apoptosis.

糖类结合蛋白(CBPS)介导多种生物学功能，如内吞作用、宿主-病原体相互作用、细胞黏附和运输以及细胞内信号转导。文献中已经报道了一些糖蛋白的确切化学结构。然而，即使是一小部分糖蛋白结构的化学合成也是非常具有挑战性的，与将它们结合到高度复杂的完整糖蛋白结构中相比，它们可能仍不具有相同的生物活性。糖共聚物(GP)由于其多价性和与多种CBPS结合的能力而被证明能够模拟糖的功能，但它们缺乏CBP的特异性。因此，发展具有精确序列控制、结构和折叠的系统GP文库，以鉴定其与人树突状细胞(DC)糖结合蛋白的特异性结合是非常有吸引力的。将研究高效的化学路线来制备精确的GP，同时通过改变碳水化合物的类型和每个聚合链的数量、链上的微结构分布和链的结构来增加编码的多样性。众所周知，这些参数中的每一个都对特定的识别、结合动力学和DC信号有巨大的影响。人体内的糖码是一种高度复杂和成熟的机制，负责各种生物识别事件。碳水化合物结合蛋白在免疫系统相关细胞上的特异性识别对改善人类健康具有至关重要的作用。该项目致力于开发一系列含有大分子的合成碳水化合物，这些大分子可以靶向树突状细胞上的特定碳水化合物结合蛋白。这种合成糖码的开发可能会打开精确地将特定细胞靶向药物输送到选定细胞的大门。此外，这种糖结构在与某些凝集素相互作用时会诱导细胞信号传递，从而可能激活细胞增殖或凋亡。

项目成果

Precisely targeted gene delivery in human skin using supramolecular cationic glycopolymers

• DOI: 10.1039/d0py00449a
• 发表时间: 2020-06-14
• 期刊: POLYMER CHEMISTRY
• 影响因子: 4.6
• 作者: Blakney, Anna K.;Liu, Renjie;Becer, C. Remzi
• 通讯作者: Becer, C. Remzi

Synthetic Glycomacromolecules of Defined Valency, Absolute Configuration, and Topology Distinguish between Human Lectins.

• DOI: 10.1021/jacsau.1c00255
• 发表时间: 2021-10-25
• 期刊: JACS Au
• 影响因子: 8
• 作者: Hartweg M;Jiang Y;Yilmaz G;Jarvis CM;Nguyen HV;Primo GA;Monaco A;Beyer VP;Chen KK;Mohapatra S;Axelrod S;Gómez-Bombarelli R;Kiessling LL;Becer CR;Johnson JA
• 通讯作者: Johnson JA

Manipulation of cytokine secretion in human dendritic cells using glycopolymers with picomolar affinity for DC-SIGN.

• DOI: 10.1039/c7sc01515a
• 发表时间: 2017-10-01
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Mitchell DA;Zhang Q;Voorhaar L;Haddleton DM;Herath S;Gleinich AS;Randeva HS;Crispin M;Lehnert H;Wallis R;Patterson S;Becer CR
• 通讯作者: Becer CR

Single-Chain Glycopolymer Folding via Host-Guest Interactions and Its Unprecedented Effect on DC-SIGN Binding.

• DOI: 10.1021/acs.biomac.8b00600
• 发表时间: 2018-06
• 期刊: Biomacromolecules
• 影响因子: 6.2
• 作者: G. Yilmaz;V. Uzunova;R. Napier;C. Becer

pH responsive glycopolymer nanoparticles for targeted delivery of anti-cancer drugs

• DOI: 10.1039/c7me00086c
• 发表时间: 2018-02
• 期刊: Circulation
• 影响因子: 37.8
• 作者: G. Yilmaz;E. Guler;Caner Geyik;B. Demir;M. Ozkan;Dilek Odaci Demirkol;S. Ozcelik;S. Timur;C. Becer