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

Pharm Res. 2000 Aug;17(8):985-90. doi: 10.1023/a:1007535506705.

Abstract

Purpose: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asialoglycoproteins / chemistry*
  • Asialoglycoproteins / metabolism
  • Carbohydrate Sequence
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism
  • Flow Cytometry
  • Galactosides / chemistry*
  • Galectins
  • Glycosides / chemistry*
  • Hemagglutinins / chemistry*
  • Hemagglutinins / metabolism
  • Lactose / chemistry*
  • Lectins / chemistry*
  • Molecular Sequence Data
  • Oligosaccharides / chemistry
  • Pharmaceutical Preparations / administration & dosage*
  • Receptors, Drug / chemistry*
  • Receptors, Drug / metabolism
  • Serum Albumin, Bovine / chemistry
  • Spectrometry, Fluorescence

Substances

  • Asialoglycoproteins
  • Carrier Proteins
  • Galactosides
  • Galectins
  • Glycosides
  • Hemagglutinins
  • Lectins
  • Oligosaccharides
  • Pharmaceutical Preparations
  • Receptors, Drug
  • Serum Albumin, Bovine
  • Lactose