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

Abstract

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 μM to 130 μM for the first step and from ~3.88 μM 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.

Heparanized chitosans: towards the third generation of chitinous biomaterials

“…A similar effect has been observed in chondroitin sulfates, natural polysaccharides that regulate important neural processes by interacting with growth factors in a sulfation dependent manner. 88,89 The identification of this structure-function relationship strengthen the hypothesis that the sulfation pattern of heparanized chitosan modulates the 3D-polysaccharidic structure which, as occurs in natural glycosaminoglycans, has a significant influence on their capacities to bind growth factors. However, it is worth noting that, in accordance with recent studies, the strong and specific binding between heparan sulfates and growth factors is not simply regulated by the sulfate distribution along the chain.…”

Heterologous production of chondroitin

“…According to its sulfation pattern, CS is mainly classified into CS-A, CS-C, CS-D, CS-E and CS-O (unsulfated chondroitin) [ 2 , 14 ]. However, novel CS disaccharide units have been discovered in natural sources (CS-F, CS-G, CS-K, CS-L, CS-M, CS-S and CS-T) [ [15] , [16] , [17] ] or chemically synthesized (CS-R, CS-U and CS-V) [18] . Considered by some authors as a type of CS, DS (CS-B) is distinguished by the presence of at least one IdoA residue, resulting from the epimerization of GlcA.…”

Strategies for Biomaterial-Based Spinal Cord Injury Repair via the TLR4-NF-κB Signaling Pathway

“…Chondroitin sulfate, similar to HA, is a polysaccharide widely distributed in ECM, synovial fluid and connective tissue, and usually attached to proteins as proteoglycans ( Tobar-Grande et al, 2013 ; Vessella et al, 2021 ). As biomaterial of cartilage tissue engineering scaffold, chondroitin sulfate exerts important effects on homeostasis of articular joints ( Tobar-Grande et al, 2013 ; Zimmermann et al, 2020 ).…”