NMR characterization and molecular modeling of fucoidan showing the importance of oligosaccharide branching in its anticomplementary activity

Abstract

Fucoidan is a potent inhibitor of the human complement system whose activity is mediated through interactions with certain proteins belonging to the classical pathway, particularly the protein C4. Branched fucoidan oligosaccharides displayed a higher anticomplementary activity as compared to linear structures. Nuclear magnetic resonance (NMR) characterization of the branched oligosaccharides and saturation transfer difference-NMR experiment of the interaction with the protein C4 allowed the identification of the glycan residues in close contact with the target protein. Transferred nuclear Overhauser effect spectroscopy experiment and molecular modeling of fucoidan oligosaccharides indicated that the presence of side chains reduces the flexibility of the oligosaccharide backbone, which thus adopts a conformation which is very close to the one recognized by the protein C4. Together, these results suggest that branching of fucoidan oligosaccharides, determining their conformational state, has a major impact on their anticomplementary activity.

Chemical Structures and Bioactivities of Sulfated Polysaccharides from Marine Algae

“…The original observations showed that fucoidan fractions from A. nodosum potently inhibit both the classical and alternative pathways in human serum [158]. Tissot and colleagues have extensively studied this activity [159,160,161,162]. It was determined that low molecular weight fucoidan fractions bind to the C1q subunit of the C1 complex that triggers complement through recognition and binding of immune complexes [162].…”

Pharmacology of Heparin and Related Drugs

“…Crystallographic studies have identified a heparin binding site on the globular region of C1q (Garlatti et al, 2010). In addition, fucoidan also exerts anticomplement activity through interacting with C4; structural studies of the interaction between C4 and a fucoidan oligosaccharide have shown that branching enhances affinity (Clément et al, 2010).…”

Therapies from Fucoidan; Multifunctional Marine Polymers

“…Fucoidans are known to be highly branched polysaccharides but the potential meaning of the branching structures in terms of bioactivity was not considered until Clement’s research of 2010 [60]. In an elegant NMR study, Clement tackles the structural heterogeneity and the random sulfation of the polysaccharide chain with relation to how they affect complement binding and inhibition.…”