Chemical synthesis is the promising way to provide homogeneous glycans. This talk will focus on how chemical synthesis has contributed to the bio-functional studies of glycans in two areas: 1) bio-dynamic studies of glycans, glycoproteins and living cells using PET and fluorescent imaging and 2) immunostimulation and immunomodulation of bacterial lipopolysaccharides, lipid As, and peptidoglycan.
PET imaging and fluorescence imaging of the labeled glycoproteins, glycodendrimers, and living cells successfully visualized the glycan-dependent bio-dynamics in whole-body system of mice or rabbits; Siaα(2,6)Gal glycans tend to retain in body, whereas asialoglycans and Siaα(2,3)Gal glycans tend to excreted rapidly through kidney and gallbladder. We also observed that bio-dynamics of glycodendrimers were significantly altered in tumor-implanted mice. Our labeling method also enabled the observation of the tumor metastases in the early stage; the glycan-dependency of the metastases was clearly visualized.
Innate immunity is the first line of the defense system against microbes. We have synthesized various bacterial glycoconjugates in order to investigate their innate immune functions. One such glycoconjugate is lipophilic terminal structure of LPS (incl. lipid A). We revealed that both acidic and lipophilic parts in lipid A are essential for the LPS activities and activation of TLR4/MD-2 are controlled by number of acidic functional groups and acylation patterns. The synthetic LPS partial structures from parasitic bacteria Helicobacter pylori and Porphyromonas gingivalis showed the antagonistic/agonistic modulation of TLR4 and selective induction of IL-18 and IL-12, both of which are associated with chronic inflammation.
Bacterial cell wall peptidoglycan (PGN) is a potent immunopotentiator. We have revealed that intracellular proteins, Nod1 and Nod2, are innate immune receptors of PGN. We have also shown that diaminopimelic acid (DAP)-type PGN containing bacteria release Nod1 ligands to the environments. We thus synthesized various PGN fragments including Nod1 and Nod2 ligands to elucidate Nod1/Nod2 functions.
