ja2104679_si_001.pdf (5.13 MB)
Glycomimetic Ligands for the Human Asialoglycoprotein Receptor
journal contribution
posted on 2012-02-01, 00:00 authored by Sreeman
K. Mamidyala, Sanjay Dutta, Boris A. Chrunyk, Cathy Préville, Hong Wang, Jane M. Withka, Alexander McColl, Timothy A. Subashi, Steven J. Hawrylik, Matthew C. Griffor, Sung Kim, Jeffrey A. Pfefferkorn, David A. Price, Elnaz Menhaji-Klotz, Vincent Mascitti, M.G. FinnThe 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.