| Autor: |
Nycholat, Corwin M., Duan, Shiteng, Knuplez, Eva, Worth, Charli, Elich, Mila, Yao, Anzhi, O’Sullivan, Jeremy, McBride, Ryan, Wei, Yadong, Fernandes, Steve M., Zhu, Zhou, Schnaar, Ronald L., Bochner, Bruce S., Paulson, James C. |
| Zdroj: |
Journal of the American Chemical Society; 20240101, Issue: Preprints |
| Abstrakt: |
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 NSANeu5Ac) combined the lead 2-naphthyl sulfonyl C-9 substituent with the preferred sulfated scaffold. The ligand 6′-O-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. |
| Databáze: |
Supplemental Index |
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