title: Glycomimetic ligands for the human asialoglycoprotein receptor.
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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Sreeman K
authors.initials: SK
authors.lastname: Mamidyala
authors.forename: Sanjay
authors.initials: S
authors.lastname: Dutta
authors.forename: Boris A
authors.initials: BA
authors.lastname: Chrunyk
authors.forename: Cathy
authors.initials: C
authors.lastname: Préville
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Jane M
authors.initials: JM
authors.lastname: Withka
authors.forename: Alexander
authors.initials: A
authors.lastname: McColl
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Subashi
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Hawrylik
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Griffor
authors.forename: Sung
authors.initials: S
authors.lastname: Kim
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Elnaz
authors.initials: E
authors.lastname: Menhaji-Klotz
authors.forename: Vincent
authors.initials: V
authors.lastname: Mascitti
authors.forename: M G
authors.initials: MG
authors.lastname: Finn
mesh_terms: D000116:Acetylgalactosamine / Q000031:analogs & derivatives / Q000737:chemistry*; D037263:Asialoglycoprotein Receptor / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D037263:Asialoglycoprotein Receptor; D008024:Ligands; D000116:Acetylgalactosamine