Triblock Glycopolymers with Two 10-mer Blocks of Activating Sugars Enhance the Activation of Acrosomal Exocytosis in Mouse Sperm

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2024-04-29 DOI:10.1021/acsbiomedchemau.4c00012
Luz C. Mendez, Mitchell Kennedy, Surita R. Bhatia and Nicole S. Sampson*, 
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Abstract

Carbohydrate recognition is imperative for the induction of sperm acrosomal exocytosis (AE), an essential phenomenon in mammalian fertilization. In mouse sperm, polynorbornene 100-mers displaying fucose or mannose moieties were effective at inducing AE. In contrast, glycopolymers exhibiting glucose sugars resulted in no AE activation. To further elucidate the role of ligand density on the activation of AE in mouse sperm, a triple-stain flow cytometry assay was employed to determine the efficacy of polynorbornene block copolymers with barbell-like sequences as initiators of AE. Triblock (ABA or ABC) copolymers were synthesized by ring-opening metathesis polymerization (ROMP) with one or two activating sugars, mannose or fucose, and one nonactivating sugar, glucose. The active ligand fractions in the polymers varied from 10, 20, or 40%. Simultaneously, random copolymers comprising 20% activating ligands were prepared to confirm the importance of ligand positionality in AE activation in mouse sperm. Polynorbornene 100-mers possessing two 10-mer blocks of activating sugars were the most effective copolymers at inducing AE with levels of AE comparable to their homopolymer counterparts and more effective than their random analogues. Small-angle X-ray scattering (SAXS) was then performed to verify that there were no differences in the conformations of the glycopolymers contributing to their varying AE activity. SAXS data analysis confirmed that all of the glycopolymers assumed semiflexible cylindrical structures with similar radii and Kuhn lengths. These findings suggest that the overall ligand density of the sugar moieties in the polymer is less important than the positionality of short blocks of high-density ligands for AE activation in mouse sperm.

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含有两个 10-mer 活化糖块的三嵌段聚糖可增强小鼠精子顶体外渗的激活作用
碳水化合物识别是诱导精子顶体外渗(AE)的必要条件,这是哺乳动物受精过程中的一个重要现象。在小鼠精子中,显示岩藻糖或甘露糖分子的聚降冰片烯 100 单体能有效诱导 AE。相比之下,含有葡萄糖的聚糖则不会激活AE。为了进一步阐明配体密度对激活小鼠精子中 AE 的作用,我们采用了一种三染色流式细胞仪测定法来确定具有钩刺状序列的聚降冰片烯嵌段共聚物作为 AE 引发剂的功效。三嵌段(ABA 或 ABC)共聚物是通过开环偏聚(ROMP)与一种或两种活化糖(甘露糖或岩藻糖)和一种非活化糖(葡萄糖)合成的。聚合物中的活性配体比例为 10%、20% 或 40%。同时,还制备了含有 20% 活性配体的无规共聚物,以证实配体位置对小鼠精子中 AE 激活的重要性。聚降冰片烯 100 嵌段具有两个 10 嵌段的活化糖,是诱导 AE 最有效的共聚物,其 AE 水平与均聚物相当,比无规类似物更有效。随后进行了小角 X 射线散射 (SAXS),以验证糖聚合物的构象是否存在差异,从而导致它们的 AE 活性各不相同。SAXS 数据分析证实,所有聚糖都具有半柔性圆柱结构,半径和库恩长度相似。这些研究结果表明,聚合物中糖分子的整体配体密度对于激活小鼠精子中的AE并没有那么重要,重要的是高密度配体短块的位置。
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来源期刊
ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
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0.00%
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0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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