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 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.
Grandjean
C
C
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. Cyrille.Grandjean@pasteur-lille.fr
Angyalosi
G
G
Loing
E
E
Adriaenssens
E
E
Melnyk
O
O
Pancré
V
V
Auriault
C
C
Gras-Masse
H
H
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D019556:COS Cells; D003713:Dendritic Cells / Q000378:metabolism; D015195:Drug Design; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D006801:Humans; D037181:Lectins, C-Type; D008351:Mannans / Q000737:chemistry / Q000378:metabolism; D008358:Mannose / Q000031:analogs & derivatives / Q000737:chemistry*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D050606:Mannose-Binding Protein-Associated Serine Proteases; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D018716:Molecular Mimicry; D011801:Quinic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D012765:Shikimic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
D000954:Antigens, Surface; D037181:Lectins, C-Type; D008351:Mannans; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011801:Quinic Acid; D012765:Shikimic Acid; C105296:MASP2 protein, human; D050606:Mannose-Binding Protein-Associated Serine Proteases; D012697:Serine Endopeptidases; D016650:Fluorescein-5-isothiocyanate; D008358:Mannose