Synthesis of sialoside analogs useful for exploring Siglec biology

CARB 17

Ola Blixt, olablixt@scripps.edu1, Brian E. Collins2, Shoufa Han2, Per Bengtson2, Hiroaki Tateno2, Nicolai Bovin3, and James Paulson2. (1) Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, (2) Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, (3) Shemyakin Institute of Bioorganic Chemistry, GSP-7, V-437, Moscow, Russia
The Siglec family of cell adhesion proteins comprise a subfamily of the immunoglobulin superfamily with variable numbers of extracellular Ig domains including a unique, homologous N-terminal Ig domain, the sialic acid binding domain. The cytoplasmic domains of the siglecs typically contain one or more tyrosine based 'ITIM' motifs characteristic of accessory proteins that regulate transmembrane signaling of cell surface receptor proteins. One of our approaches to dissect the biology of the siglecs is to employ novel carbohydrate probes that modulate their function. We use chemo-enzymatic approaches to synthesize sialoside analogs recognized by siglecs. Their utility ranging from potent mono- or multivalent probes to monovalent sialic acid analogs that can be fed to cells and incorporated into cell surface glycoproteins to add chemical functionality or alter the affinity of sialoside ligands for binding cell surface siglecs. This presentation will cover synthetic strategies, screening of sialoside inhibitors and their use as biological probes for investigating roles of siglecs in cell signaling.