Lectin-mediated drug targeting: selection of valency, sugar type (Gal/Lac), and spacer length for cluster glycosides as parameters to distinguish ligand binding to C-type asialoglycoprotein receptors and galectins.
OBJECTIVE
Common oligosaccharides of cellular glycoconjugates are ligands for more than one type of endogenous lectin. Overlapping specificities to beta-galactosides of C-type lectins and galectins can reduce target selectivity of carbohydrate-ligand-dependent drug targeting. The purpose of this study is to explore distinct features of ligand presentation and structure for design of cluster glycosides to distinguish between asialoglycoprotein-specific (C-type) lectins and galectins.


METHODS
Extent of binding of labeled sugar receptors to two types of matrix-immobilized (neo)glycoproteins and to cells was evaluated in the absence and presence of competitive inhibitors. This panel comprised synthetic mono-, bi-, and trivalent glycosides with two spacer lengths and galactose or lactose as ligand part.


RESULTS
In contrast to C-type lectins of hepatocytes and macrophages, bi- and trivalent glycosides do not yield a notable glycoside cluster effect for galectins-1 and -3. Also, these Ca2+-independent galactoside-binding proteins prefer to home in on lactose-bearing glycosides relative to galactose as ligand, while spacer length requirements were rather similar.


CONCLUSIONS
Trivalent cluster glycosides with Gal/GalNAc as ligand markedly distinguish between C-type lectins and galectins. Undesired side reactivities to galectins for C-type lectin drug delivery will thus be minimal.
André
S
S
Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, Germany.
Frisch
B
B
Kaltner
H
H
Desouza
D L
DL
Schuber
F
F
Gabius
H J
HJ
D001212:Asialoglycoproteins / Q000737:chemistry* / Q000378:metabolism; D002240:Carbohydrate Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D005434:Flow Cytometry; D005697:Galactosides / Q000737:chemistry*; D037161:Galectins; D006027:Glycosides / Q000737:chemistry*; D006388:Hemagglutinins / Q000737:chemistry* / Q000378:metabolism; D007785:Lactose / Q000737:chemistry*; D037102:Lectins / Q000737:chemistry*; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D011955:Receptors, Drug / Q000737:chemistry* / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000737:chemistry; D013050:Spectrometry, Fluorescence
D001212:Asialoglycoproteins; D002352:Carrier Proteins; D005697:Galactosides; D037161:Galectins; D006027:Glycosides; D006388:Hemagglutinins; D037102:Lectins; D009844:Oligosaccharides; D004364:Pharmaceutical Preparations; D011955:Receptors, Drug; D012710:Serum Albumin, Bovine; D007785:Lactose