Glycomimetic Ligands for the Human Asialoglycoprotein Receptor

Citations Over TimeTop 10% of 2012 papers

Abstract

The asialoglycoprotein receptor (ASGPR) is a high-capacity galactose-binding receptor expressed on hepatocytes that binds its native substrates with low affinity. More potent ligands are of interest for hepatic delivery of therapeutic agents. We report several classes of galactosyl analogues with varied substitution at the anomeric, C2-, C5-, and C6-positions. Significant increases in binding affinity were noted for several trifluoromethylacetamide derivatives without covalent attachment to the protein. A variety of new ligands were obtained with affinity for ASGPR as good as or better than that of the parent N-acetylgalactosamine, showing that modification on either side of the key C3,C4-diol moiety is well tolerated, consistent with previous models of a shallow binding pocket. The galactosyl pyranose motif therefore offers many opportunities for the attachment of other functional units or payloads while retaining low-micromolar or better affinity for the ASGPR.

Related Papers

• → Highly α- and β-Selective Radical C-Glycosylation Reactions Using a Controlling Anomeric Effect Based on the Conformational Restriction Strategy. A Study on the Conformation−Anomeric Effect− Stereoselectivity Relationship in Anomeric Radical Reactions(2001)164 cited
• → D-Galactose 6-phosphate: anomeric distribution and analysis of its synthesis from D-galactose and polyphosphoric acid(1981)6 cited
• → Synthesis of novel phosphonate analogue of Kdo as a tool for the design of potent inhibitors for lipopolysaccharide biosynthesis(1994)8 cited
• → A Novel Glycosylation of 3-Deoxy-D-glycero-D-galacto-2-nonulosonic Acid (KDN) via in Situ Pyranose-Furanose Rearrangement.(1997)6 cited
• → A new hybrid (experimental–theoretical) quantitative method for detection of relative anomer concentrations in water(2015)2 cited