TY - JOUR
T1 - On-chip synthesis and screening of a sialoside library yields a high affinity ligand for Siglec-7
AU - Rillahan, Cory D.
AU - Schwartz, Erik
AU - Rademacher, Christoph
AU - McBride, Ryan
AU - Rangarajan, Janani
AU - Fokin, Valery V.
AU - Paulson, James C.
PY - 2013/7/19
Y1 - 2013/7/19
N2 - 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.
AB - 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.
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U2 - 10.1021/cb400125w
DO - 10.1021/cb400125w
M3 - Article
C2 - 23597400
AN - SCOPUS:84880567768
VL - 8
SP - 1417
EP - 1422
JO - ACS Chemical Biology
JF - ACS Chemical Biology
SN - 1554-8929
IS - 7
ER -