Stereochemistry Drives the Macromolecular Conformation and Biological Activity of Glycopolymers

IF 10.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Muhammad Waqas Ishaq, , , Parisa Farzeen, , , Lindsay R. Vaughn, , , Daniel J. Stone, , , Sanket A. Deshmukh, , and , Cassandra E. Callmann*, 
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Abstract

Chirality plays a fundamental role in biology, where stereochemical information governs how molecules fold, interact, and function. While the effects of stereochemistry are well-established for small molecules and natural biomacromolecules, less is known about how it shapes the properties of synthetic, biomimetic polymers. In this study, we explore how backbone and glycan stereochemistry influences conformation, physical interactions, and biological behavior in water-soluble glycopolymers. Using ring opening metathesis polymerization (ROMP), we synthesized precision glycopolymers (PGPs) from two diastereomeric norbornenyl moieties (endo and exo) and monosaccharides (glucose, galactose, and mannose). Despite having nearly identical molecular and macromolecular compositions, the resulting PGPs displayed major differences in their physical and biological properties. Glycopolymers with β-linkages showed distinct circular dichroism (CD) signals, and exo-derived backbones displayed more hydrophobic local environments, as confirmed by all-atom molecular dynamics simulations and dye interaction studies. These structural differences had clear functional consequences. exo-PGPs bound plant lectins more rapidly and with higher avidity, whereas endo-PGPs showed greater selectivity toward human galectin-3, stronger inhibition of cholera toxin, and enhanced uptake into 4T1 triple-negative breast cancer cells. Together, these findings provide the first demonstration of biological activity in endo-derived glycopolymers and establish backbone stereochemistry as a key design element that encodes macromolecular behavior in biologically relevant contexts.

Subtle changes in polymer stereochemistry drive major differences in macromolecular conformation and biological function, revealing stereochemistry as a key element in glycomaterial design.

立体化学驱动糖共聚物的大分子构象和生物活性
手性在生物学中起着重要作用,其中立体化学信息决定了分子如何折叠、相互作用和功能。虽然立体化学对小分子和天然生物大分子的影响是公认的,但对它如何塑造合成的仿生聚合物的特性却知之甚少。在这项研究中,我们探讨了主链和聚糖立体化学如何影响水溶性糖共聚物的构象、物理相互作用和生物行为。利用开环复分解聚合(ROMP),我们从两个非对映异构体降冰片烯基(内端和外端)和单糖(葡萄糖、半乳糖和甘露糖)合成了精密糖共聚物(pgp)。尽管具有几乎相同的分子和大分子组成,所得到的pgp在物理和生物特性上表现出重大差异。全原子分子动力学模拟和染料相互作用研究证实,具有β键的糖共聚物表现出明显的圆二色性(CD)信号,外源骨架表现出更疏水的局部环境。这些结构上的差异有明显的功能后果。外显式pgps结合植物凝集素的速度更快,活性更高,而内显式pgps对人半乳糖凝集素-3有更高的选择性,对霍乱毒素有更强的抑制作用,并增强了对4T1三阴性乳腺癌细胞的吸收。总之,这些发现首次证明了内源性糖共聚物的生物活性,并建立了骨架立体化学作为生物学相关背景下编码大分子行为的关键设计元素。聚合物立体化学的细微变化导致了大分子构象和生物功能的重大差异,揭示了立体化学在糖材料设计中的关键作用。
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来源期刊
ACS Central Science
ACS Central Science Chemical Engineering-General Chemical Engineering
CiteScore
25.50
自引率
0.50%
发文量
194
审稿时长
10 weeks
期刊介绍: ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.
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