Title
Design and synthesis of novel N-acetylgalactosamine-terminated glycolipids for targeting of lipoproteins to the hepatic asialoglycoprotein receptor
Author
TNO Preventie en Gezondheid
Rensen, P.C.N.
van Leeuwen, S.H.
Sliedregt, L.A.J.M.
van Berkel, T.J.C.
Biessen, E.A.L.
Publication year
2004
Abstract
A novel glycolipid has been prepared that contains a cluster glycoside with an unusually high affinity for the asialoglycoprotein receptor (ASGPr) and a bile acid moiety that mediates stable incorporation into lipidic particles. The glycolipid spontaneously associated with low-density lipoproteins (LDL) and high-density lipoproteins (HDL) within human and murine plasma, and loading of lipoproteins with this glycolipid resulted in an efficient dose-dependent recognition and uptake of LDL and HDL by the liver (and not by spleen) upon intravenous injection into wild-type mice. Preinjection with asialoorosomucoid largely inhibited the uptake, establishing that both HDL and LDL were selectively recognized and processed by the ASGPr on liver parenchymal cells. Finally, repeated intravenous administration of the glycolipid to hyperlipidemic LDL receptor-deficient mice evoked an efficient and persistent cholesterol-lowering effect. These results indicate that the glycolipid may be a promising alternative for the treatment of hyperlipidemic patients who do not respond sufficiently to current cholesterol-lowering therapies. Chemicals / CAS: Acetylgalactosamine, 31022-50-1; Anticholesteremic Agents; Asialoglycoprotein Receptor; Blood Proteins; Glycolipids; Iodine Radioisotopes; Lipoproteins, HDL; Lipoproteins, LDL; Receptors, LDL.
Subject
Biomedical Research
asialoglycoprotein receptor
asialoorosomucoid
bile acid
glycolipid
high density lipoprotein
hypocholesterolemic agent
low density lipoprotein
n acetylgalactosamine
animal cell
article
binding affinity
chemical structure
dose response
drug design
drug synthesis
human
human cell
hyperlipidemia
liver cell
liver parenchyma
male
mouse
nonhuman
protein targeting
protein transport
receptor binding
wild type
Acetylgalactosamine
Animals
Anticholesteremic Agents
Asialoglycoprotein Receptor
Blood Proteins
Drug Design
Glycolipids
Humans
Hyperlipidemias
Iodine Radioisotopes
Isotope Labeling
Lipoproteins, HDL
Lipoproteins, LDL
Liver
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein Binding
Receptors, LDL
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http://resolver.tudelft.nl/uuid:2869ccd1-0fea-4d70-8c0b-9303f44f465c
DOI
https://doi.org/10.1021/jm049481d
TNO identifier
238089
ISSN
0022-2623
Source
Journal of Medicinal Chemistry, 47 (47), 5798-5808
Document type
article