Oligosaccharides and Viral Infection: Human Milk Oligosaccharides versus Algal Fucan-Type Polysaccharides

Summary

Norovirus infections belong to the most common causes of human gastroenteritis worldwide, and epidemic outbreaks are responsible for hundreds of thousands deaths annually. In humans, noroviruses are known to bind to gastrointestinal epithelia via recognition of blood group-active mucin-type O-glycans. Besides vaccine-based approaches to combat the virus, one of the alternative strategies to prevent noro- virus infections is based on food additives, e.g., human milk oligosaccharides (HMOs).
HMOs represent an ideal source of potential competitors of viral glycan receptors, which mimick the structures of blood group-active mucin-type O-glycans. The trisaccharide 2-fucosyllactose (2′FL) is able to block norovirus binding quite efficiently and has reached market approval as a save food additive. In addition, we could provide evidence for other milk oligosaccharides in the high-mass range that exert even stronger competitive effects on norovirus binding to gastric mucins [1]. During these studies, we observed that oligovalency of fucose in hepta- to decasaccharides promotes competitive effects on norovirus binding. This became most evident when L-fucose cyclodextrin-based dendrimers with varying degrees of substitution were compared with respect to their competitive activity [1]. High valency of α-L-fucose with no relationship to blood group structures is also a feature of natural polysaccharides belonging to the group of polyfucoses or fucans.

Algal fucoidans are present in several orders, mainly Fucales and Laminariales, and they exist either as a homopolymer of fucose or as a heteropolysaccharide. Fucoidans can have their central chains composed of (1→3)-linked α-L-fucose or of Fuc-α(1-3)Gal repeating units as in Undaria pinnatifida, or they are composed of repeating (1→3) and
(1→4)-linked fucose (Fucus species). Sulfate residues are found at high densities, as every second fucose can be substituted at C2 and/or C4.

Among fucoidans, those of the brown algae have previously attracted much attention, as they were claimed to exert a series of health beneficial effects. Like other sulfated polysaccharides, fucoidans can inhibit virus infection of cells. This has been demonstrated for Herpes simplex, cytomegalovirus, and human immunodeficiency virus as well as bovine viral diarrhea virus, probably by competing with cell surface heparan sulfate for binding to the virus, a mechanism which is strictly dependent on sulfation of the polysaccharide.

Considering the involvement of α-L-fucose residues in epithelial receptors, their high valency-associated binding avidity far surpasses the low-affinity (though specific) interactions of monovalent blood group- active HMOs, which is reflected in IC50 values in the millimolar range (for example, LNFP-I: >50 mM) [1]. We here report for the first time on competitive anti-norovirus effects exerted by α-L-fucose of fucoidans derived from different sources and demonstrate that their inhibitory capacity is retained in desulfated and fragmented low-molecular- weight processing products. Avidity-based increases in efficiency, as reflected in the IC50 values, are in the order of 100-fold fucose: >50 mM, 2′FL: 25 mM, fucoidan from Fucus vesiculosus: 250 µM. Insight into structural aspects was obtained by X-ray analysis of P-domain dimer oligofucose cocrystals, which confirmed low-affinity interaction of single fucose with the capsid protein. NMR-based structural work on various forms of low-molecular-mass fucoidans prepared from F. vesiculosus and U. pinnatifida are ongoing.

In an animal model, blocking tests with various fucoidan preparations affecting viral binding to gastrointestinal epithelia have been performed by virion-challenging experiments in oyster. In targeting currently untreatable norovirus infections, this study provides first steps towards a prophylactic food additive that is produced from algal species.

Reference
1 Hanisch FG, Hansman GS, Morozov V, et al: Avidity of α-fucose on human milk
oligosaccharides and blood group-unrelated oligo/polyfucoses is essential for potent norovirus-binding targets. J Biol Chem 2018;293:11955–11965.