title: Synthesis of multivalent glycoconjugates containing the immunoactive LELTE peptide: effect of glycosylation on cellular activation and natural killing by human peripheral blood mononuclear cells.
abstract: Pentapeptide diacidic sequence LELTE, derived from the mycobacterial heat shock protein hsp65, has been recently identified as a "danger" signal of the immune system effective via specific binding to the universal leukocyte triggering receptor CD69. This sequence is not active per se, only after its presentation within the multivalent environment of its parent protein, or after artificial dimerization using a standard bifunctional reagents. Here we describe an entirely new way of presenting of this peptide based on its attachment to a cyclopeptide RAFT scaffold (K-K-K-P-G)(2) through the epsilon-amino group of lysine residues, alone or in combination with the carbohydrate epitope alphaGalNAc. The ability of such RAFT scaffolds to precipitate the target CD69 receptor or to activate CD69-positive cells is enhanced in compounds 2 and 4 possessing combined peptide/carbohydrate expression. Compounds 2 and 4 are highly efficient activators of natural killer lymphocytes, but they are completely inactive from the point of view of activation-induced apoptosis of lymphocytes by the target cells. These unique properties make the combined peptide/carbohydrate RAFTs highly suitable for future evaluation in animal tumor therapies in vivo and predict them to be readily available and efficient immunoactivators.
authors.affiliation: Département de Chimie Moléculaire, UMR CNRS 5250 and ICMG FR 2607, Université Joseph Fourier, BP53, 38041 Grenoble Cedex 9, France. olivier.renaudet@ujf-grenoble.fr
authors.forename: Olivier
authors.initials: O
authors.lastname: Renaudet
authors.forename: Karel
authors.initials: K
authors.lastname: Krenek
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bossu
authors.forename: Pascal
authors.initials: P
authors.lastname: Dumy
authors.forename: Alan
authors.initials: A
authors.lastname: Kádek
authors.forename: David
authors.initials: D
authors.lastname: Adámek
authors.forename: Ondrej
authors.initials: O
authors.lastname: Vanek
authors.forename: Daniel
authors.initials: D
authors.lastname: Kavan
authors.forename: Radek
authors.initials: R
authors.lastname: Gazák
authors.forename: Miroslav
authors.initials: M
authors.lastname: Sulc
authors.forename: Karel
authors.initials: K
authors.lastname: Bezouska
authors.forename: Vladimír
authors.initials: V
authors.lastname: Kren
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D006001:Glycoconjugates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D010091:Oximes / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D006001:Glycoconjugates; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009842:Oligopeptides; D010091:Oximes; D010456:Peptides, Cyclic; D000099192:CD69 Antigens