Glycomimetic ligands for the human asialoglycoprotein receptor |
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Authors: | Mamidyala Sreeman K Dutta Sanjay Chrunyk Boris A Préville Cathy Wang Hong Withka Jane M McColl Alexander Subashi Timothy A Hawrylik Steven J Griffor Matthew C Kim Sung Pfefferkorn Jeffrey A Price David A Menhaji-Klotz Elnaz Mascitti Vincent Finn M G |
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Affiliation: | Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. |
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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. |
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