Grandjean C, Angyalosi G, Loing E, Adriaenssens E, Melnyk O, Pancré V, Auriault C, Gras-Masse H
Laboratoire de Synthèse, Structure et Fonction des Biomolécules, UMR 8525, Institut de Biologie/Institut Pasteur de Lille et CNRS 1, rue du Professeur Calmette, BP447, 59021 Lille Cédex, France.
Chembiochem. 2001 Oct 1;2(10):747-57. doi: 10.1002/1439-7633(20011001)2:10<747::AID-CBIC747>3.0.CO;2-O.
The mannose receptor mediates the internalization of a wide range of molecules or microorganisms in a pattern recognition manner. Therefore, it represents an attractive entry for specific drug, gene, or antigen delivery to macrophages and dendritic cells. In an attempt to design novel effective synthetic mannose receptor ligands, quinic and shikimic acid were selected as putative mannose mimics on the basis of X-ray crystallographic data from the related rat mannose-binding lectin. As the mannose receptor preferentially binds to molecules displaying several sugar residues, fluorescein-labeled cluster quinic and shikimic acid derivatives with valencies of two to eight were synthesized. Their mannose receptor mediated uptake was assayed on monocyte-derived human dendritic cells by cytofluorimetric analysis. Mannose-receptor specificity was further assessed by competitive inhibition assays with mannan, by confocal microscopy analysis, and by expression of the mannose receptor in transfected Cos-1 cells. Constructs derived from both quinic and shikimic acid were efficiently recognized by the mannose receptor with an optimum affinity for the molecules with a valency of four. As a result, commercially available quinic and shikimic acids appear as stable mannose bioisosteres, which should prove valuable tools for specific cell delivery.
甘露糖受体以模式识别的方式介导多种分子或微生物的内化。因此，它是将特定药物、基因或抗原递送至巨噬细胞和树突状细胞的一个有吸引力的切入点。为了设计新型有效的合成甘露糖受体配体，基于相关大鼠甘露糖结合凝集素的X射线晶体学数据，选择奎尼酸和莽草酸作为假定的甘露糖模拟物。由于甘露糖受体优先结合显示多个糖残基的分子，因此合成了具有二至八价的荧光素标记的簇状奎尼酸和莽草酸衍生物。通过细胞荧光分析在单核细胞衍生的人树突状细胞上测定它们由甘露糖受体介导的摄取。通过与甘露聚糖的竞争性抑制试验、共聚焦显微镜分析以及转染的Cos-1细胞中甘露糖受体的表达，进一步评估甘露糖受体的特异性。源自奎尼酸和莽草酸的构建体均能被甘露糖受体有效识别，对四价分子具有最佳亲和力。结果，市售的奎尼酸和莽草酸表现为稳定的甘露糖生物电子等排体，这应该是用于特定细胞递送的有价值的工具。
