Novel hyperbranched glycomimetics recognized by the human mannose receptor: Quinic or shikimic acid derivatives as mannose bioisosteres

The mannose receptor mediates the internalization of a wide range of molecu les or microorganisms in a pattern recognition manner. Therefore, it repres ents an attractive entry for specific drug, gene, or antigen delivery to ma crophages and dendritic cells. In an attempt to design novel effective synt hetic mannose receptor ligands, quinic and shikimic acid were selected as p utative 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 mo nocyte-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 mann ose receptor in transfected Cos-1 cells. Constructs derived from both quini c and shikimic acid were efficiently recognized by the mannose receptor wit h an optimum affinity for the molecules with a valency of four. As a result , commercially available quinic, and shikimic acids appear as stable mannos e bioisosteres, which should prove valuable tools for specific cell deliver y.