A Sulfonamide Sialoside Analogue for Targeting Siglec-8 and -F on Immune Cells

Abstract

The Siglec family of cell surface receptors have emerged as attractive targets for cell-directed therapies due to their restricted expression on immune cells, endocytic properties, and ability to modulate receptor signaling. Human Siglec-8, for instance, has been identified as a therapeutic target for the treatment of eosinophil and mast cell disorders. A promising strategy to target Siglecs involves the use of liposomal nanoparticles with a multivalent display of Siglec ligands. A key challenge for this approach is the identification of a high affinity ligand for the target Siglec. Here, we report the development of a ligand of Siglec-8 and its closest murine functional orthologue Siglec-F that is capable of targeting liposomes to cells expressing Siglec-8 or -F. A glycan microarray library of synthetic 9-<i>N</i>-sulfonyl sialoside analogues was screened to identify potential lead compounds. The best ligand, 9-<i>N</i>-(2-naphthyl-sulfonyl)-Neu5Acα2-3-[6-<i>O</i>-sulfo]-Galβ1-4GlcNAc (6'-<i>O</i>-sulfo ^NSANeu5Ac) combined the lead 2-naphthyl sulfonyl C-9 substituent with the preferred sulfated scaffold. The ligand 6'-<i>O</i>-sulfo ^NSANeu5Ac was conjugated to lipids for display on liposomes to evaluate targeted delivery to cells. Targeted liposomes showed strong in vitro binding/uptake and selectivity to cells expressing Siglec-8 or -F and, when administered to mice, exhibit in vivo targeting to Siglec-F⁺ eosinophils.