Rillahan CD, Schwartz E, Rademacher C, McBride R, Rangarajan J, Fokin VV, Paulson JC. (2013) On-Chip Synthesis and Screening of a Sialoside Library Yields a High Affinity Ligand for Siglec-7. ACS Chem Biol. PMID: 23597400; PMCID: PMC3751994
The Siglec family of sialic acid-binding proteins are differentially expressed on white blood cells of the immune system and represent an attractive class of targets for cell-directed therapy. Nanoparticles decorated with high-affinity Siglec ligands show promise for delivering cargo to Siglec-bearing cells, but this approach has been limited by a lack of ligands with suitable affinity and selectivity. Building on previous work employing solution-phase sialoside library synthesis and subsequent microarray screening, we herein report a more streamlined ‘on-chip’ synthetic approach. By printing a small library of alkyne sialosides and subjecting these to ‘on-chip’ click reactions, the largest sialoside analogue library to date was generated. Siglec-screening identified a selective Siglec-7 ligand, which when displayed on liposomal nanoparticles, allows for targeting of Siglec-7+ cells in peripheral human blood. In silico docking to the crystal structure of Siglec-7 provides a rationale for the affinity gains observed for this novel sialic acid analogue.
Link to journal: http://pubs.acs.org/journal/acbcct