Synthesis of High-Mannose Oligosaccharide Analogues through Click Chemistry: True Functional Mimics of Their Natural Counterparts Against Lectins?
Synthesis of High-Mannose Oligosaccharide Analogues through Click Chemistry: True Functional Mimics of Their Natural Counterparts Against Lectins?
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DOI：
10.1002/chem.201405481
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发表时间：
2015-01-26
影响因子：
4.3
通讯作者：
Djedaini-Pilard, Florence
中科院分区：
文献类型：
--
作者：
Francois-Heude, Marc;Mendez-Ardoy, Alejandro;Djedaini-Pilard, Florence
末端“高甘露糖低聚糖”参与广泛的生物和病理过程，从精子-卵子融合到流感和人类免疫缺陷病毒感染。尽管作出了许多努力，但它们的合成仍然非常具有挑战性，实际上是该领域的一个主要瓶颈。虽然甘露糖基序的多价呈现在各种支架上已被证明是一种成功的方式来干扰涉及高甘露糖低聚糖的识别过程，但这种结构无法再现对各种蛋白质受体(凝集素)和抗体的亲和力的细微差异，这些凝集素和抗体容易与天然配体结合。在这里，我们报道了一类功能性的高甘露糖低聚糖模拟物，通过用三唑环取代一些内部的甘露糖低聚糖单元，不仅再现了甘露糖基的末端展示，而且再现了核心结构和分支模式。这种分子设计可以通过“点击”连接策略来实现，从而大大降低了合成成本。用酶联凝集素分析法研究了新的“点击”高甘露糖低聚糖模拟两种甘露糖特异凝集素，即植物凝集素刀豆蛋白A(ConA)和人巨噬细胞甘露糖受体(RhMMR)的结合亲和力，发现其趋势与天然低聚糖的相同。针对ConA的量热测定和X-射线结构数据支持这一结论，即这些化合物不仅是另一类多价甘露糖苷，而且是真正的高甘露糖低聚糖的“结构模拟”。
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.