Synthetic N-acetyl-D-glucosamine based fully branched tetrasaccharide, a mimetic of the endogenous ligand for CD69, activates CD69+ killer lymphocytes upon dimerization via a hydrophilic flexible linker.
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.
Kovalová
Anna
A
Institute of Organic Chemistry and Biochemistry, VVI, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Ledvina
Miroslav
M
Saman
David
D
Zyka
Daniel
D
Kubícková
Monika
M
Zídek
Lukás
L
Sklenár
Vladimír
V
Pompach
Petr
P
Kavan
Daniel
D
Bílý
Jan
J
Vanek
Ondrej
O
Kubínková
Zuzana
Z
Libigerová
Martina
M
Ivanová
Ljubina
L
Antolíková
Mária
M
Mrázek
Hynek
H
Rozbeský
Daniel
D
Hofbauerová
Katerina
K
Kren
Vladimír
V
Bezouska
Karel
K
D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002240:Carbohydrate Sequence; D045744:Cell Line, Tumor; D019281:Dimerization; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D000099192:CD69 Antigens
D000117:Acetylglucosamine; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D007155:Immunologic Factors; D037181:Lectins, C-Type; D008024:Ligands; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009844:Oligosaccharides; D011994:Recombinant Proteins; D000099192:CD69 Antigens