Synthetic N-acetylglucosamine based fully branched tetrasaccharide, a mimetic of the endogenous ligand for CD69, activates CD69+ NK cells and killer lymphocytes upon dimerization via a hydrophilic flexible linker
| Autoři | |
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| Rok publikování | 2010 |
| Druh | Článek v odborném periodiku |
| Časopis / Zdroj | Journal of Medicinal Chemistry |
| Fakulta / Pracoviště MU | |
| Citace | |
| Obor | Biochemie |
| Klíčová slova | Lymphocyte activation; receptors for carbohydrates; crosslinking; natural killer cells; tumor immunotherapies |
| Popis | Based on the highly branched ovomucoid-type undecasaccharide that has been shown previously to constitute a physiological ligand for CD69 leukocyte receptor, a systematic investigation of smaller oligosaccharide mimetics has been performed based on the linear and branched N-acetylhexosamine homooligomers prepared synthetically using hitherto unexplored reaction schemes. The systematic structure activity studies revealed the tetrasaccharide GlcNAcb1-3(GlcNAcb1-4)(GlcNAcb1-6)GlcNAc (compound 52) and its a-benzyl-derivative 49 as the best ligand for CD69 with IC50 as high as 10-9 M, thus approaching the affinity of the classical high-affinity ligand GlcNAc17BSA. Compound 68, GlcNAc tetrasaccharide dimerized through a hydrophilic flexible linker, turned out to be effective in activation of CD69+ lymphocytes. It also proved efficient in enhancing natural killing in vitro, decreasing the growth of tumors in vivo, and activating the CD69+ tumor infiltrating lymphocytes examined ex vivo. This compound thus represents a candidate for carbohydrate-based immunomodulators with a promising antitumor potential. |
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