Sulfation Code and Conformational Plasticity of l-Iduronic Acid Homo-Oligosaccharides Mimic the Biological Functions of Heparan Sulfate

Recently, the activity in heparan sulfate (HS) has led to the discovery of many drug molecules that have the potential to impact both medical science and human health. However, structural diversity and synthetic challenges impede the progress of HS research. Here we show that synthetic HS mimics can be engineered to produce many of the functions of native HS. HS mimics were synthesized from an L-Iduronic acid (IdoA) scaffold, which was homooligomerized by stereoselective α-1,4-glycosylation and regioselective sulfation. The exhaustive NMR analysis of these HS mimics, using both NOE and vicinal 3JH-H coupling constants, confirmed that sulfation at the O-4 enhances the 1C4 geometry population at the corresponding ring. Interestingly, the 1C4 conformer becomes almost exclusive upon additional sulfation at O-2. Microarray and SPR analysis of HS mimics with different growth factors established that oligosaccharide length, sulfation code, and exclusive IdoA conformation synergistically affect the specificity and activity of growth factors. Particularly, 4-O-sulfated IdoA disaccharide had a strong binding affinity to vascular endothelial growth factor (VEGF165) and therefore, modulated endothelial cell proliferation, migration, and angiogenesis. These results establish the potential of sulfated IdoA oligosaccharides to be used as structurally well-defined HS mimics as they provide several functions of native HS.