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首页> 外文期刊>Chemistry: A European journal >Synthesis of High-Mannose Oligosaccharide Analogues through Click Chemistry: True Functional Mimics of Their Natural Counterparts Against Lectins?
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Synthesis of High-Mannose Oligosaccharide Analogues through Click Chemistry: True Functional Mimics of Their Natural Counterparts Against Lectins?

机译：通过单击化学合成高甘露糖寡糖类似物：天然抗凝集素的真正功能模拟物吗？

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摘要

Terminal "high-mannose oligosaccharides" are involved in a broad range of biological and pathological processes, from sperm-egg fusion to influenza and human immunodeficiency virus infections. In spite of many efforts, their synthesis continues to be very challenging and actually represents a major bottleneck in the field. Whereas multivalent presentation of mannopyranosyl motifs onto a variety of scaffolds has proven to be a successful way to interfere in recognition processes involving high-mannose oligosaccharides, such constructs fail at reproducing the subtle differences in affinity towards the variety of protein receptors (lectins) and antibodies susceptible to binding to the natural ligands. Here we report a family of functional high-mannose oligosaccharide mimics that reproduce not only the terminal mannopyranosyl display, but also the core structure and the branching pattern, by replacing some inner mannopyranosyl units with triazole rings. Such molecular design can be implemented by exploiting "click" ligation strategies, resulting in a substantial reduction of synthetic cost. The binding affinities of the new "click" high-mannose oligosaccharide mimics towards two mannose specific lectins, namely the plant lectin concanavalin A (ConA) and the human macrophage mannose receptor (rhMMR), have been studied by enzyme-linked lectin assays and found to follow identical trends to those observed for the natural oligosaccharide counterparts. Calorimetric determinations against ConA, and X-ray structural data support the conclusion that these compounds are not just another family of multivalent manno-sides, but real "structural mimics" of the high-mannose oligosaccharides.
机译：末端“高甘露糖寡糖”涉及广泛的生物学和病理学过程，从精卵融合到流感和人类免疫缺陷病毒感染。尽管付出了许多努力，但它们的合成仍然非常具有挑战性，实际上代表了该领域的主要瓶颈。尽管将甘露吡喃糖基基序多价呈现在各种支架上是干扰涉及高甘露糖寡糖的识别过程的成功方法，但此类构建体无法再现对多种蛋白质受体（凝集素）和抗体的亲和力的细微差异易与天然配体结合。在这里，我们报告了一系列功能性高甘露糖寡糖模拟物，它们不仅可以复制末端甘露糖吡喃糖基展示，而且还可以通过用三唑环取代一些内部甘露糖吡喃糖基单元来复制核心结构和分支模式。这种分子设计可以通过利用“点击”连接策略来实现，从而大大降低了合成成本。新的“点击”高甘露糖寡糖模拟物对两种甘露糖特异性凝集素，即植物凝集素伴刀豆球蛋白A（ConA）和人巨噬细胞甘露糖受体（rhMMR）的结合亲和力已通过酶联凝集素测定法进行了研究并发现遵循与天然低聚糖对应物相同的趋势。针对ConA的量热法测定和X射线结构数据支持以下结论：这些化合物不仅是另一类多价甘露糖苷，而且是高甘露糖寡糖的真正“结构模拟物”。

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