1. SyntheticN-Acetyl-<scp>d</scp>-glucosamine Based Fully Branched Tetrasaccharide, a Mimetic of the Endogenous Ligand for CD69, Activates CD69+Killer Lymphocytes upon Dimerization via a Hydrophilic Flexible Linker
- Author
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Jan Bílý, Vladimír Sklenář, Lukáš Žídek, Petr Pompach, Mária Antolíková, Daniel Rozbeský, Daniel Kavan, Martina Libigerová, Karel Bezouška, Vladimír Křen, Zuzana Kubínková, David Šaman, Ljubina Ivanova, Anna Kovalová, Monika Kubíčková, Daniel Zyka, Miroslav Ledvina, Ondřej Vaněk, Kateřina Hofbauerová, and Hynek Mrázek
- Subjects
Antigens, Differentiation, T-Lymphocyte ,Models, Molecular ,Stereochemistry ,Molecular Sequence Data ,Melanoma, Experimental ,Oligosaccharides ,Antineoplastic Agents ,In Vitro Techniques ,Ligands ,Lymphocyte Activation ,Acetylglucosamine ,Mice ,Antigens, CD ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Immunologic Factors ,Tetrasaccharide ,Lectins, C-Type ,Receptor ,chemistry.chemical_classification ,Chemistry ,Molecular Mimicry ,Oligosaccharide ,Ligand (biochemistry) ,Recombinant Proteins ,In vitro ,Rats ,Killer Cells, Natural ,Mice, Inbred C57BL ,Carbohydrate Sequence ,Molecular Medicine ,Female ,Drug Screening Assays, Antitumor ,Dimerization ,Linker ,Ex vivo ,NK Cell Lectin-Like Receptor Subfamily B - Abstract
On the basis of the highly branched ovomucoid-type undecasaccharide that had been shown previously to be an endogenous ligand for CD69 leukocyte receptor, a systematic investigation of smaller oligosaccharide mimetics was performed based on linear and branched N-acetyl-d-hexosamine homooligomers prepared synthetically using hitherto unexplored reaction schemes. The systematic structure-activity studies revealed the tetrasaccharide GlcNAcbeta1-3(GlcNAcbeta1-4)(GlcNAcbeta1-6)GlcNAc (compound 52) and its alpha-benzyl derivative 49 as the best ligand for CD69 with IC(50) as high as 10(-9) M. This compound thus approaches the affinity of the classical high-affinity neoglycoprotein ligand GlcNAc(23)BSA. Compound 68, GlcNAc tetrasaccharide 52 dimerized through a hydrophilic flexible linker, turned out to be effective in activating 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 is thus a candidate for carbohydrate-based immunomodulators with promising antitumor potential.
- Published
- 2010