Design and synthesis of novel N-acetylgalactosamine-terminated glycolipids for targeting of lipoproteins to the hepatic asialoglycoprotein receptor

Rensen, P.C.N.; Leeuwen, S.H. van; Sliedregt, L.A.J.M.; Berkel, T.J.C. van; Biessen, E.A.L.

Design and synthesis of novel N-acetylgalactosamine-terminated glycolipids for targeting of lipoproteins to the hepatic asialoglycoprotein receptor

article

2004

Rensen, P.C.N.

Leeuwen, S.H. van

Sliedregt, L.A.J.M.

Berkel, T.J.C. van

Biessen, E.A.L.

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.

Topics

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

TNO Identifier

238089

Repository link

https://resolver.tno.nl/uuid:2869ccd1-0fea-4d70-8c0b-9303f44f465c

ISSN

00222623

Source

Journal of Medicinal Chemistry, 47(23), pp. 5798-5808.

Pages

5798-5808

Files

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Design and synthesis of novel N-acetylgalactosamine-terminated glycolipids for targeting of lipoproteins to the hepatic asialoglycoprotein receptor

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