On-Chip Synthesis and Screening of a Sialoside Library Yields a High Affinity Ligand for Siglec‑7

• Published in: ACS chemical biology 2013-07, Vol.8 (7), p.1417-1422
• Main Authors: Rillahan, Cory D, Schwartz, Erik, Rademacher, Christoph, McBride, Ryan, Rangarajan, Janani, Fokin, Valery V, Paulson, James C
• Format: Article
• Language: English
• Subjects: Antigens, Differentiation, Myelomonocytic - chemistry; Antigens, Differentiation, Myelomonocytic - metabolism; Binding Sites; Crystallography, X-Ray; Drug Delivery Systems; Drug Evaluation, Preclinical; Fluoresceins - chemistry; Humans; Jurkat Cells; Lectins - chemistry; Lectins - metabolism; Ligands; Liposomes - chemistry; Microarray Analysis; Molecular Structure; Sialic Acids - chemistry; Small Molecule Libraries - chemistry
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/cb400125w

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.