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Sasayama, S; Moriya, Kayoko; Chiba, Taku; Matsumoto, Takayuki; Hayashi, Hidetoshi; Hayashi, Akiko; Onozaki, Kikuo

doi:10.1023/a:1007181929405

Cited by 7 publications

(1 citation statement)

References 37 publications

(39 reference statements)

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“…In kidney a slight preference for the uptake of the sialylated neoglycoproteins was found, favoring the α2,3-sialylated N -glycan over the α2,6-isomer (Table ). Enhanced tissue concentrations were also seen for neoglycointerleukin-1α carrying a spacer-bound derivative of N -acetylneuraminic acid . Hence, sialylation may not generally lead to a prolonged circulatory half-life of N -glycan-exposing neoglycoproteins in mice.…”

Section: Resultsmentioning

confidence: 99%

Structure−Activity Profiles of Complex Biantennary Glycans with Core Fucosylation and with/without Additional α2,3/α2,6 Sialylation: Synthesis of Neoglycoproteins and Their Properties in Lectin Assays, Cell Binding, and Organ Uptake

et al. 2001

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The consideration of oligosaccharides and glycoconjugates as biopharmaceuticals is an emerging topic in drug design. Chemoenzymatic synthesis of N-glycans was performed to examine the influence of N-glycan core fucosylation on lectin-binding properties and biodistribution. As a first step in a systematic comparison of N-glycans, the core fucose moiety was chemically introduced into a complex-type biantennary heptasaccharide azide. After deprotection and attachment of a spacer, the terminal sections of the N-glycan were elongated enzymatically. Conversion of the amino group in the spacer to an isothiocyanate gave derivatives allowing convenient ligand attachment to bovine serum albumin (BSA). The resulting neoglycoproteins contained an average of 2.9-4.6 chains per carrier molecule. Relative to unsubstituted biantennary complex-type N-glycans, the core fucosylation appears to favor the extended orientation of the alpha 1,6-arm. This was deduced from an up to 5-fold alteration of affinity for lectins in solid-phase assays. Marked differences were also found for cell surface binding of cultured tumor cells, for staining of tumor cells in lung sections, and in organ distribution. In vivo, the alpha 2,6-sialylated neoglycoproteins showed a reduced serum half-life in mice relative to the alpha 2,3-sialylated isomer and the non-fucosylated congeners. These results support the notion that changing the shape of a glycan provides a promising strategy to optimize the affinity of protein-carbohydrate interactions. Overall, our study underscores the importance of chemoenzymatic synthesis to define the effect of chain orientation on the ligand properties of N-glycans.

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Section: Resultsmentioning

confidence: 99%

Structure−Activity Profiles of Complex Biantennary Glycans with Core Fucosylation and with/without Additional α2,3/α2,6 Sialylation: Synthesis of Neoglycoproteins and Their Properties in Lectin Assays, Cell Binding, and Organ Uptake

et al. 2001

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Synthesis of glycosylated human tumor necrosis factor α coupled with N-acetylneuraminic acid

Hayashi

Chiba

Hayashi

et al. 2006

Cancer Immunol Immunother

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In order to study the effect of glycosylation on its biological activities, and to develop TNFalpha with less deleterious effects, recombinant human TNFalpha was chemically coupled with N-acetylneuraminic acid (NeuAc). NeuAc with C9 spacer was coupled to TNFalpha by acyl azide method. Two glycosylated TNFalphas, designated L NeuAc-TNFalpha and H NeuAc-TNFalpha, were purified by anion-exchange chromatography. NeuAc coupling to TNFalpha was confirmed by lectin blotting. Average number of carbohydrate molecules introduced per molecule of L NeuAc-TNFalpha and H NeuAc-TNFalpha were estimated to be 1.0 and 1.5, respectively. We examined a variety of TNFalpha activities in vitro, including antiproliferative or cytotoxic activities to tumor cells, proliferative effect on fibroblast cells, stimulatory effects on IL-6 production by melanoma cells and NF-kappaB activation in hepatoma cells. L NeuAc-TNFalpha and H NeuAc-TNFalpha exhibited reduced activities about 1/3 and 1/10 as compared to native TNFalpha in all the activities performed in vitro.

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N-acetylneuraminic acid coupled human recombinant TNFα exhibits enhanced anti-tumor activity against Meth-A fibrosarcoma and reduced toxicity

Hayashi

Chiba

et al. 2006

Cancer Immunol Immunother

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In order to study the effect of glycosylation on its biological activities and to develop tumor necrosis factor alpha (TNFalpha) with less deleterious effects, N-acetylneuraminic acid (NeuAc) with a C9 spacer was chemically coupled to human recombinant TNFalpha. NeuAc-coupled TNFalpha (NeuAc-TNFalpha) exhibited reduced activities in vitro by about threefold compared to native TNFalpha. In this study, we examined a variety of TNFalpha activities in vivo. NeuAc-TNFalpha reduced activities in the up-regulation of serum levels of IL-6 and NOx, but comparable activity as native TNFalpha in the down-regulation of the serum level of glucose. However, NeuAc-TNFalpha was more potent than TNFalpha in the up-regulation of the serum level of serum amyloid A (SAA). NeuAc-TNFalpha was less toxic to mice. In addition, NeuAc-TNFalpha exhibited an augmented anti-tumor activity against Meth-A fibrosarcoma without hemorrhagic necrosis. These results indicate that coupling with NeuAc enabled us to develop neoglycoTNFalpha with selective activities in vivo, including enhanced anti-tumor activity but reduced toxicity.

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Untitled

Cited by 7 publications

References 37 publications

Structure−Activity Profiles of Complex Biantennary Glycans with Core Fucosylation and with/without Additional α2,3/α2,6 Sialylation: Synthesis of Neoglycoproteins and Their Properties in Lectin Assays, Cell Binding, and Organ Uptake

Structure−Activity Profiles of Complex Biantennary Glycans with Core Fucosylation and with/without Additional α2,3/α2,6 Sialylation: Synthesis of Neoglycoproteins and Their Properties in Lectin Assays, Cell Binding, and Organ Uptake

Synthesis of glycosylated human tumor necrosis factor α coupled with N-acetylneuraminic acid

N-acetylneuraminic acid coupled human recombinant TNFα exhibits enhanced anti-tumor activity against Meth-A fibrosarcoma and reduced toxicity

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