We have recently identified a new class of high affinity ligands for CD69 leukocyte membrane receptor, carboxylated calixarenes. Of the three compounds investigated here, thiacalix[4]arene had the highest affinity for CD69 in direct binding assays, and proved to be the most specific inhibitor of CD69 identified so far in receptor precipitation and cellular activation experiments. Carboxylated calixarenes also proved effective at protection of CD69(high) lymphocytes from apoptosis triggered by a multivalent ligand or antibody. Thus, carboxylated calixarenes set a new paradigm for noncarbohydrate ligands for CD69 making them attractive for protection of killer cells in combined animal tumor therapies.

• MeSH
• apoptóza MeSH
• CD antigeny metabolismus   MeSH
• diferenciační antigeny T-lymfocytů metabolismus   MeSH
• kalixareny chemie   metabolismus   MeSH
• krysa rodu rattus MeSH
• kyseliny karboxylové chemie   MeSH
• lektiny typu C metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• publikace stažené z tisku MeSH

Human placental beta1,4-galactosyltransferase-I (EC 2.4.1.38) transfers the galactosyl moiety from UDP-Gal to various GlcNAc or Glc acceptors in vivo. Here, we describe the construction of its Y284L mutant as a His(6)propeptide-catbeta4GalT1 construct, in which the Gal-transferase activity was totally abolished in favor of its GalNAc-transferase activity. We used this mutant in the synthesis of three mono- and bivalent LacdiNAc glycomimetics with good yields. These compounds proved to be powerful ligands of two activation receptors of natural killer cells, NKR-P1 and CD69. A synthetic bivalent tethered di-LacdiNAc is the best currently known precipitation agent for both of these receptors and has promising potential for the development of immunoactive glycodrugs.

• MeSH
• bakteriální proteiny metabolismus   MeSH
• Campylobacter jejuni enzymologie   MeSH
• CD antigeny metabolismus   MeSH
• diferenciační antigeny T-lymfocytů metabolismus   MeSH
• epimerázy sacharidů metabolismus   MeSH
• galaktosyltransferasy genetika   metabolismus   MeSH
• glykokonjugáty biosyntéza   chemická syntéza   metabolismus   MeSH
• laktosa analogy a deriváty   biosyntéza   chemická syntéza   metabolismus   MeSH
• lektinové receptory NK-buněk - podrodina B metabolismus   MeSH
• lektiny typu C MeSH
• lidé MeSH
• mutace MeSH
• placenta enzymologie   MeSH
• substrátová specifita MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• publikace stažené z tisku MeSH

• Publikační typ
• abstrakty MeSH

A series of calixarenes substituted with 2-acetamido-2-deoxy-beta-D-glucopyranose linked by a thiourea spacer was prepared and tested for binding activity to heterogeneously expressed activation receptors of the rat natural killer cells NKR-P1, and the receptor CD69 (human NK cells, macrophages). In the case of NKR-P1, the binding affinity of beta-D-GlcNAc-substituted calixarenes carrying two or four sugar units was in a good agreement with the inhibitory potencies of the linear chitooligomers (chitobiose to chitotetraose) reported previously. The influence of GlcNAc substitution of the calixarene skeleton on binding affinity for CD69 receptor was more profound and the 5,11,17,23-tetrakis[N-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-thioureido]-25,26,27,28-tetrapropoxycalix[4]arene (cone) (1) proved to be the best CD69 ligand identified to date. Lower GlcNAc substitution led to dramatic decrease of the binding activity (by about 1.5 order of magnitude per one GlcNAc unit). The immunostimulating activity results with the newly synthesized GlcNAc tetramers on calixarene scaffolds exhibited stimulation of natural cytotoxicity of human PBMC in concentrations 10(-4) and 10(-8)M. These calix-sugar compounds were superior to the previously tested PAMAM-GlcNAc(8)5.

• MeSH
• acetylglukosamin analogy a deriváty   farmakologie   MeSH
• aktivace lymfocytů účinky léků   MeSH
• antitumorózní látky farmakologie   chemická syntéza   MeSH
• buňky NK imunologie   účinky léků   MeSH
• financování organizované MeSH
• glykokonjugáty chemická syntéza   terapeutické užití   MeSH
• kalixareny chemie   MeSH
• kinetika MeSH
• leukocyty mononukleární účinky léků   MeSH
• lidé MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• nádory farmakoterapie   imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• Check Tag
• lidé MeSH