Deciphering Structural Determinants in Chondroitin Sulfate Binding to FGF-2: Paving the Way to Enhanced Predictability of their Biological Functions

Controlling chondroitin sulfates (CSs) biological functions to exploit their interesting potential biomedical applications requires a comprehensive understanding of how the specific sulfate distribution along the polysaccharide backbone can impact in their biological activities, a still challenging issue. To this aim, herein, we have applied an “holistic approach” recently developed by us to look globally how a specific sulfate distribution within CS disaccharide epitopes can direct the binding of these polysaccharides to growth factors. To do this, we have analyzed several polysaccharides of marine origin and semi‐synthetic polysaccharides, the latter to isolate the structure‐activity relationships of their rare, and even unnatural, sulfated disaccharide epitopes. SPR studies revealed that all the tested polysaccharides bind to FGF‐2 (with exception of CS‐8, CS‐12 and CS‐ 13) according to a model in which the CSs first form a weak complex with the protein, which is followed by maturation to tight binding with kD ranging affinities from ~ 1.31 M to 130 M for the first step and from ~ 3.88 M to 1.8 nM for the second one. These binding capacities are, interestingly, related with the surface charge of the 3D‐structure that is modulated by the particular sulfate distribution within the disaccharide repeating‐units