| 孙现慧,张家彬.化学通报,2026,89(7):865-873,804. |
| 唾液酸类似物库的化学-酶法构建及其对血凝素的识别特性 |
| Chemo-enzymatic Construction of a Sialic Acid Analog Library and Their Recognition Properties Toward Hemagglutinins |
| 投稿时间：2026-04-14 修订日期：2026-04-29 |
| DOI： |
| 中文关键词: 甲型流感病毒 血凝素 化学酶法 唾液酸类似物 糖芯片 |
| 英文关键词:Influenza A virus Hemagglutinin Sialic acid analogs Glycan microarray One-pot multi-enzyme synthesis |
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| 摘要点击次数: 226 |
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| 中文摘要: |
| 流感病毒血凝素（HA）在演化过程中受体识别特性不断改变，且天然唾液酸与HA的亲和力极弱，限制了对其识别过程的研究与干预。本研究旨在构建结构多样性的非天然唾液酸类似物库，探究化学修饰对不同演化阶段毒株的HA蛋白识别模式的影响。采用化学酶法合成策略，利用一锅多酶法（OPME）精准构建α-2,6糖苷键，通过引入1,3-丙二硫醇/三乙胺体系，实现叠氮基团与苄氧羰基的正交选择性还原，得到系列氨基糖骨架。基于该通用骨架，通过平行化衍生在唾液酸C-5和C-9位点引入不同的磺酰基修饰，构建了包含18种非天然唾液酸类似物的化合物库。糖芯片分析显示，化合物3a（二糖）和5c（三糖）对2019-H1N1 HA蛋白均表现出强结合活性（3a提升约200倍，5c峰值约25000 RFU），且5c对2009-H1N1亦有显著结合。分子对接结果揭示，相同C-9位修饰不同糖链骨架下识别特性下的差异，表明配体识别受末端修饰、骨架长度及HA蛋白的协同调控，本研究为针对HA的高亲和力配体设计提供了先导结构和实验依据。 |
| 英文摘要: |
| The receptor-binding properties of influenza virus hemagglutinin (HA) undergo continuous evolution, and the inherent weak affinity between natural sialic acids and HA limits the effective study and intervention of viral recognition processes. This study aims to construct a structurally diverse library of non-natural sialic acid analogs to explore the impact of chemical modifications on the recognition patterns of influenza strains at different evolutionary stages. A chemo-enzymatic synthesis strategy was employed, utilizing a one-pot multienzyme (OPME) system to precisely construct ɑ-2,6-glycosidic linkages. By introducing a 1,3-propanedithiol/triethylamine system, the orthogonal selective reduction of azide groups in the presence of benzyloxycarbonyl (Cbz) protecting groups was achieved, yielding a series of universal amino-sugar scaffolds. Based on these scaffolds, a library comprising 18 non-natural sialic acid analogs was constructed through parallel derivatization, incorporating acyl and sulfonyl groups with varying electronic and hydrophobic properties at the C-5 and C-9 positions. Glycan microarray analysis revealed that compounds 3a (disaccharide) and 5c (trisaccharide) exhibited strong binding activity against the 2019-H1N1 HA protein, with 3a showing an approximately 200-fold increase in fluorescence intensity compared to the natural disaccharide control and 5c displaying a peak RFU value of approximately 25000. Moreover, 5c also showed significant binding to the 2009-H1N1 HA protein. Molecular docking further revealed that the same C-9 modification led to markedly different activities on different glycan backbones, indicating that ligand recognition is synergistically regulated by the terminal modification, the glycan chain length, and the specific HA protein. These findings provide lead structures and experimental evidence for the design of high-affinity ligands targeting HA. |
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