Synthetic Glycomacromolecules of Defined Valency, Absolute Configuration, and Topology Distinguish between Human Lectins.
Synthetic Glycomacromolecules of Defined Valency, Absolute Configuration, and Topology Distinguish between Human Lectins.
复制标题
DOI：
10.1021/jacsau.1c00255
复制
发表时间：
2021-10-25
期刊：
影响因子：
8
通讯作者：
Johnson JA
中科院分区：
文献类型：
--
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
碳水化合物结合蛋白（凝集素）在细胞识别和信号传导中起着至关重要的作用，包括病原体结合和先天免疫。因此，靶向凝集素，特别是免疫细胞表面的凝集素，可以促进免疫学和药物的发现。凝集素通常是低聚的；因此，许多最有效的配体都是多价的。一种有效的凝集素靶向策略是在聚合物主链上显示单个聚糖表位的多个拷贝；然而，这种多价配体的缺点是它们不能区分具有单糖结合选择性的凝集素（例如甘露糖结合凝集素），因为它们通常缺乏分子精度。在这里，我们描述了迭代指数增长（IEG）合成策略的发展，该策略可以方便地获得精确定义和可调大小达22.5 kDa的合成糖大分子，组成，拓扑结构和绝对构型。我们合成了12种独立的甘露糖基化“糖- eggmers”，并筛选了它们与一组甘露糖糖结合的免疫凝集素（DC-SIGN、DC-SIGNR、MBL、SP-D、langerin、dectin-2、mincle和DEC-205）结合。在许多情况下，糖- iegmers具有不同的长度，立体化学和拓扑依赖性凝集素结合偏好。为了理解这些差异，我们利用分子动力学和密度泛函理论模拟了八聚糖-聚乙二醇聚合物，揭示了糖-聚乙二醇聚合物的立体化学和拓扑结构对溶液结构的巨大影响，揭示了选择性凝集素结合中构象多样性和手性识别之间的相互作用。配体的功能也可以通过化学取代来控制：通过调整结合DC-SIGN的糖- iegmers的侧链，我们可以通过改变它们的聚集状态来改变它们的细胞运输。这些结果突出了精确合成低聚物/聚合物合成选择性生物靶向的力量，推动了为特定免疫或其他治疗应用量身定制的下一代糖大分子的发展。
Carbohydrate-binding proteins (lectins) play vital roles in cell recognition and signaling, including pathogen binding and innate immunity. Thus, targeting lectins, especially those on the surface of immune cells, could advance immunology and drug discovery. Lectins are typically oligomeric; therefore, many of the most potent ligands are multivalent. An effective strategy for lectin targeting is to display multiple copies of a single glycan epitope on a polymer backbone; however, a drawback to such multivalent ligands is they cannot distinguish between lectins that share monosaccharide binding selectivity (e.g., mannose-binding lectins) as they often lack molecular precision. Here, we describe the development of an iterative exponential growth (IEG) synthetic strategy that enables facile access to synthetic glycomacromolecules with precisely defined and tunable sizes up to 22.5 kDa, compositions, topologies, and absolute configurations. Twelve discrete mannosylated “glyco-IEGmers” are synthesized and screened for binding to a panel of mannoside-binding immune lectins (DC-SIGN, DC-SIGNR, MBL, SP-D, langerin, dectin-2, mincle, and DEC-205). In many cases, the glyco-IEGmers had distinct length, stereochemistry, and topology-dependent lectin-binding preferences. To understand these differences, we used molecular dynamics and density functional theory simulations of octameric glyco-IEGmers, which revealed dramatic effects of glyco-IEGmer stereochemistry and topology on solution structure and reveal an interplay between conformational diversity and chiral recognition in selective lectin binding. Ligand function also could be controlled by chemical substitution: by tuning the side chains of glyco-IEGmers that bind DC-SIGN, we could alter their cellular trafficking through alteration of their aggregation state. These results highlight the power of precision synthetic oligomer/polymer synthesis for selective biological targeting, motivating the development of next-generation glycomacromolecules tailored for specific immunological or other therapeutic applications.
登录
查看更多内容
影响因子：
15
作者：
Golder MR;Jiang Y;Teichen PE;Nguyen HV;Wang W;Milos N;Freedman SA;Willard AP;Johnson JA
通讯作者：
Johnson JA
影响因子：
15
作者：
Becer, C. Remzi;Gibson, Matthew I.;Geng, Jin;Ilyas, Rebecca;Wallis, Russell;Mitchell, Daniel A.;Haddleton, David M.
通讯作者：
Haddleton, David M.
影响因子：
21.8
作者：
Barnes, Jonathan C.;Ehrlich, Deborah J. C.;Johnson, Jeremiah A.
通讯作者：
Johnson, Jeremiah A.
影响因子：
4.6
作者：
Binauld, Sandra;Damiron, Denis;Drockenmuller, Eric
通讯作者：
Drockenmuller, Eric
影响因子：
3.8
作者：
Ji, X;Olinger, GG;Spear, GT
通讯作者：
Spear, GT