Open AccessA Sulfonamide Sialoside Analogue for Targeting Siglec-8 and -F on Immune Cells
Author(s) -
Corwin M. Nycholat,
Shiteng Duan,
Eva Knuplez,
Charli Worth,
Mila Elich,
Anzhi Yao,
Jeremy A. O’Sullivan,
Ryan McBride,
Yadong Wei,
Steve M. Fernandes,
Zhou Zhu,
Ronald L. Schnaar,
Bruce S. Bochner,
James C. Paulson
Publication year - 2019
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.9b05769
Subject(s) - siglec , chemistry , receptor , cd22 , ligand (biochemistry) , microbiology and biotechnology , cell , biochemistry , biology , cd19
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- N -sulfonyl sialoside analogues was screened to identify potential lead compounds. The best ligand, 9- N -(2-naphthyl-sulfonyl)-Neu5Acα2-3-[6- O -sulfo]-Galβ1-4GlcNAc (6'- O -sulfo NSA Neu5Ac) combined the lead 2-naphthyl sulfonyl C-9 substituent with the preferred sulfated scaffold. The ligand 6'- O -sulfo NSA Neu5Ac 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.