title: On-chip synthesis and screening of a sialoside library yields a high affinity ligand for Siglec-7.
abstract: 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.
authors.affiliation: Departments of Cell and Molecular Biology, ‡Chemical Physiology, and §Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Cory D
authors.initials: CD
authors.lastname: Rillahan
authors.forename: Erik
authors.initials: E
authors.lastname: Schwartz
authors.forename: Christoph
authors.initials: C
authors.lastname: Rademacher
authors.forename: Ryan
authors.initials: R
authors.lastname: McBride
authors.forename: Janani
authors.initials: J
authors.lastname: Rangarajan
authors.forename: Valery V
authors.initials: VV
authors.lastname: Fokin
authors.forename: James C
authors.initials: JC
authors.lastname: Paulson
mesh_terms: D015214:Antigens, Differentiation, Myelomonocytic / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D005452:Fluoresceins / Q000737:chemistry*; D006801:Humans; D019169:Jurkat Cells; D037102:Lectins / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008081:Liposomes / Q000737:chemistry; D046228:Microarray Analysis; D015394:Molecular Structure; D012794:Sialic Acids / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry*
chemical_list: D015214:Antigens, Differentiation, Myelomonocytic; D005452:Fluoresceins; D037102:Lectins; D008024:Ligands; D008081:Liposomes; C402206:SIGLEC7 protein, human; D012794:Sialic Acids; D054852:Small Molecule Libraries