Abstract
Chitin, a polymer of β-(1→4)-linked N-acetyl-d-glucosamine, is one of the main polysaccharide components of the fungal cell wall. Its N-deacetylated form, chitosan, is enzymatically produced in the cell wall by chitin deacetylases. It exerts immunomodulative, anti-inflammatory, anti-cancer, anti-bacterial, and anti-fungal activities with various medical applications. To study the immunobiological properties of chitosan oligosaccharides, we synthesized a series of β-(1→4)-linked N-acetyl-d-glucosamine oligomers comprising 3, 5, and 7 monosaccharide units equipped with biotin tags. The key synthetic intermediate employed for oligosaccharide chain elongation, a disaccharide thioglycoside, was prepared by orthogonal glycosylation of a 4-OH thioglycoside acceptor with a glycosyl trichloroacetimidate bearing the temporary 4-O-tert-butyldimethylsilyl group. The use of silyl protection suppressed aglycon transfer and provided a high yield for the target disaccharide donor. Using synthesized chitosan oligomers, as well as previously obtained chitin counterparts, the immunobiological relationship between these synthetic oligosaccharides and RAW 264.7 cells was studied in vitro. Evaluation of cell proliferation, phagocytosis, respiratory burst, and Th1, Th2, Th17, and Treg polarized cytokine expression demonstrated effective immune responsiveness and immunomodulation in RAW 264.7 cells exposed to chitin- and chitosan-derived oligosaccharides. Macrophage reactivity was accompanied by significant inductive dose- and structure-dependent protective Th1 and Th17 polarization, which was greater with exposure to chitosan- rather than chitin-derived oligosaccharides. Moreover, no antiproliferative or cytotoxic effects were observed, even following prolonged 48 h exposure. The obtained results demonstrate the potent immunobiological activity of these synthetically prepared chito-oligosaccharides.
Highlights
The fungal cell wall protects the cell from environmental stresses and is essential for cell morphogenesis and pathogenicity (Bowman and Free, 2006; Gow and Hube, 2012; Erwig and Gow, 2016; Gow et al, 2017)
As well as previously prepared chitin counterparts (Yudina et al, 2016), we demonstrate the immunomodulative activities of synthetically prepared chitin- and chitosan-derived oligosaccharide formulas of various lengths and evaluate the structure–immunomodulation relationship
We recently described the synthesis of 2-aminoethyl glycosides of chito-oligomers containing 3, 5, and 7 N-acetyl-D-glucosamine residues (Yudina et al, 2015) and their biotinylated derivatives 28–30 (Scheme 3) (Yudina et al, 2016)
Summary
The fungal cell wall protects the cell from environmental stresses and is essential for cell morphogenesis and pathogenicity (Bowman and Free, 2006; Gow and Hube, 2012; Erwig and Gow, 2016; Gow et al, 2017). It comprises mostly polysaccharides of different types (Latgé, 2010) that account for ∼90% of the cell wall, each carrying out Immunobiological Activity of Chito-Oligosaccharides a specific biological function. Cell wall polysaccharides are engaged in the pathogen-associated molecular patterns associated with interactive crosstalk between immunocytes and immune sensing of the host organism, triggering various immune responses—innate and/or adaptive
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