Novel Hyperbranched Glycomimetics Recognized by the Human Mannose Receptor: Quinic or Shikimic Acid Derivatives as Mannose Bioisosteres

Abstract

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.

Design and Creativity in Synthesis of Multivalent Neoglycoconjugates

“…Another investigation targeting the mannose receptor expressed by the human dendritic cell (DC-SIGN) has been presented by Grandjean et al but adding carbohydrate mimicry to the multivalent concept. 344,368 As with the strategy just described, quinic and shikimic acid derivatives used as mannose bioisosteres have been linked to dendritic L-lysine scaffolds to afford novel hyperbranched glycomimetics (Fig. 55).…”

Clustered carbohydrates in synthetic vaccines

“…50 The same group designed a complementary strategy where the tetravalent system presenting quinic acids was covalently linked via a hydrazone ligation to a multilamellar lipidic vesicles vectors. 51 These “onion” vesicles presented a mean size about 200 nm and contained surface aldehydes to be functionalized with the hydrazine presented at the tail of the multivalent system.…”

Shikimic acid, a mannose bioisostere, promotes hair growth with the induction of anagen hair cycle

“…When MR is activated, it can trigger a protective pathway against autoimmune diseases 26 . MR selectively recognizes mannose, N-acetyl glucosamine, and fucose residue 13,14 . SA acts as a mannose bioisostere and interacts with the cell surface MR 5,20 .…”

“…We investigated the molecular mechanism through which SA promotes hair growth. SA is known to interact with MR on the cell surface, which could activate myeloid differentiation primary response 88 (MyD88) 9,13,14 . The downstream pathway of MyD88 is known as p38 MAPK and CREB, which are known to promote cell survival and prevent apoptosis 31,32 .…”

“…It is known that SA acts as a mannose bioisostere of the mannose receptor (MR, CD206), which is found in fibroblasts and keratinocytes 13–15 . MR is a carbohydrate-binding receptor, which is known to have an antigen-presenting function; however, recently, it has been reported that MR may affect cell signaling by participating in the p38 mitogen-activated protein kinase (MAPK)-cAMP response element-binding protein (CREB) pathway 14,16 .…”