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

Purpose. Common oligosaccharides of cellular glycoconjugates are ligands fo r more than one type of endogenous lectin. Overlapping specificities to bet a-galactosides of C-type lectins and galectins can reduce target selectivit y of carbohydrate-ligand-dependent drug targeting. The purpose of this stud y is to explore distinct features of ligand presentation and structure for design of cluster glycosides to distinguish between asialoglycoprotein-spec ific (C-type) lectins and galectins. Methods. Extent of binding of labeled sugar receptors to two types of matri x-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 l actose 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 fo r galectins-1 and -3. Also, these Ca2+-independent galactoside binding prot eins 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 markedl y distinguish between C-type lectins and galectins. Undesired side reactivi ties to galectins for C-type lectin drug delivery will thus be minimal.