Stereochemical Control Yields Mucin Mimetic Polymers.
Stereochemical Control Yields Mucin Mimetic Polymers.
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立体化学控制产生粘蛋白模拟聚合物。
DOI：
10.1021/acscentsci.0c01569
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发表时间：
2021-04-28
影响因子：
18.2
通讯作者：
Kiessling LL
中科院分区：
文献类型：
--
作者：
Kruger AG;Brucks SD;Yan T;Cárcarmo-Oyarce G;Wei Y;Wen DH;Carvalho DR;Hore MJA;Ribbeck K;Schrock RR;Kiessling LL
除海绵外，所有动物都会产生粘液。在整个动物界，这种水凝胶可以调节表面润湿、粘度和抵御微生物的能力。粘液水凝胶的主要成分是粘蛋白——采用延伸线性结构的高分子量O-糖蛋白。糖基化是粘蛋白功能不可或缺的一部分，但产生其有利生物活性的其他特征尚不清楚。我们假设粘蛋白的扩展构象对于其阻断微生物毒力表型的能力至关重要。为了检验这一假设，我们开发了合成的粘蛋白模拟物，它概括了聚糖的密集显示和粘蛋白的形态。我们改变了开环复分解聚合（ROMP）中的催化剂，以生成含有顺式或反式烯烃的取代的降冰片烯衍生的糖聚合物。基于烯丙基应变的聚合物的构象分析表明，顺式而不是反式聚（降冰片烯）糖聚合物将采用模拟粘蛋白的线性结构。我们的聚合物和天然纯化的 Muc2、Muc5AC 和 Muc5B 粘蛋白的高分辨率原子力显微照片显示，顺式聚合物采用扩展的粘蛋白样结构。顺式聚合物在溶液中保留了这种结构，并且比反式类似物更易溶于水。与粘蛋白的线性形态一致，顺式糖聚合物是细菌毒力因子霍乱毒素的更有效的结合剂。我们的研究结果强调了聚合物主链在粘蛋白替代物设计中的重要性，并强调了延伸的粘蛋白主链对于抑制毒力的重要性。具有顺式烯烃几何主链的碳水化合物取代聚合物采用扩展构象，模仿天然粘蛋白的三维结构和毒素抑制能力。
All animals except sponges produce mucus. Across the animal kingdom, this hydrogel mediates surface wetting, viscosity, and protection against microbes. The primary components of mucus hydrogels are mucins—high molecular weight O-glycoproteins that adopt extended linear structures. Glycosylation is integral to mucin function, but other characteristics that give rise to their advantageous biological activities are unknown. We postulated that the extended conformation of mucins is critical for their ability to block microbial virulence phenotypes. To test this hypothesis, we developed synthetic mucin mimics that recapitulate the dense display of glycans and morphology of mucin. We varied the catalyst in a ring-opening metathesis polymerization (ROMP) to generate substituted norbornene-derived glycopolymers containing either cis- or trans-alkenes. Conformational analysis of the polymers based on allylic strain suggested that cis- rather than trans-poly(norbornene) glycopolymers would adopt linear structures that mimic mucins. High-resolution atomic force micrographs of our polymers and natively purified Muc2, Muc5AC, and Muc5B mucins revealed that cis-polymers adopt extended, mucin-like structures. The cis-polymers retained this structure in solution and were more water-soluble than their trans-analogs. Consistent with mucin’s linear morphology, cis-glycopolymers were more potent binders of a bacterial virulence factor, cholera toxin. Our findings highlight the importance of the polymer backbone in mucin surrogate design and underscore the significance of the extended mucin backbone for inhibiting virulence. Carbohydrate-substituted polymers with backbones of the cis-alkene geometry adopt an extended conformation, mimicking natural mucin’s three-dimensional structure and toxin inhibition capacity.
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影响因子：
15
作者：
Keitz, Benjamin K.;Fedorov, Alexey;Grubbs, Robert H.
通讯作者：
Grubbs, Robert H.
影响因子：
18.2
作者：
Canton I;Warren NJ;Chahal A;Amps K;Wood A;Weightman R;Wang E;Moore H;Armes SP
通讯作者：
Armes SP
影响因子：
9.2
作者：
Caldara, Marina;Friedlander, Ronn S.;Kavanaugh, Nicole L.;Aizenberg, Joanna;Foster, Kevin R.;Ribbeck, Katharina
通讯作者：
Ribbeck, Katharina
影响因子：
4.8
作者：
Axelsson, MAB;Asker, N;Hansson, GC
通讯作者：
Hansson, GC
影响因子：
6.2
作者：
Authimoolam, Sundar P.;Vasilakes, Andrew L.;Shah, Nihar M.;Puleo, David A.;Dziubla, Thomas D.
通讯作者：
Dziubla, Thomas D.