Heterobifunctional ligands: practical chemoenzymatic synthesis of a cell adhesive glycopeptide that interacts with both selectins and integrins.
An efficient and practical synthesis of cell adhesive glycopeptides exhibiting unique properties as a novel type of modulator of cellular recognition is described. A nonnatural glycopeptide 1 composed of sialyl Lewis x and Lys-Gly-Arg-Gly-Asp-Ser that interacts with both selectins and integrins has been systematically synthesized by combined chemical and enzymatic strategy. It is suggested that glycopeptide 1 showed much higher affinity with P-selectin (K(a) = 6.6 x 10(7) M(-1)) and E-selectin (K(a) = 4.5 x 10(5) M(-1)) than sialyl Lewis x. This compound also inhibited a specific interaction between human integrin beta(1) and its monoclonal antibody more effectively than the tetrapeptide Arg-Gly-Asp-Ser. Interestingly, it was demonstrated by surface plasmon resonance analysis that this heterobifunctional glycopeptide exhibited a capacity to form stable complexes with P-selectin and integrin beta(1) concurrently. It is also suggested that this activity can be used for the inhibition of integrin-mediated adhesion of activated helper T cells onto collagen-coated plates as a cell migration model. These results indicate that the chemoenzymatic hybridization strategy of different biological functions of carbohydrates and peptides is a new concept for designing potent glycoconjugates as antiinflammatory and anticancer metastasis reagents.
Division of Immunoregulation, Research Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
M
M
Matsuda
S
S
Nishimura
F
F
Nakajima
T
T
Nishimura
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D002240:Carbohydrate Sequence; D002448:Cell Adhesion; D002478:Cells, Cultured; D019040:E-Selectin / Q000737:chemistry; D005647:Fucosyltransferases; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D019012:Integrin beta1 / Q000737:chemistry / Q000276:immunology; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D019087:Selectins / Q000737:chemistry / Q000378:metabolism*; D012799:Sialyltransferases; D020349:Surface Plasmon Resonance; D018418:Th2 Cells / Q000378:metabolism; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
D000911:Antibodies, Monoclonal; D019040:E-Selectin; D006020:Glycopeptides; D007202:Indicators and Reagents; D019012:Integrin beta1; D016023:Integrins; D008024:Ligands; D009842:Oligopeptides; D009844:Oligosaccharides; D019087:Selectins; C423342:lysyl(3-carbamidopropyl O-(5-acetamido-3,5-dideoxygalacto-2-nonulopyranosylonic acid)-2-3-galactopyranosyl-1-4-O-(fucopyranosyl-1-3)-O-2-acetamido-2-deoxyglucopyranoside)-glycyl-arginyl-glycyl-aspartyl-serine; D005647:Fucosyltransferases; C031692:galactoside 3-fucosyltransferase; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase