Introduction of a sugar unit at either the O5 or O6 position of various neamine derivatives in excellent selectivity and yields is described here. Application to the synthesis of kanamycin analogues ...is also highlighted.
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The posttranslational modification of therapeutic proteins with terminal sialic acids is one means of improving their circulating half-life, thereby improving their efficiency. We have developed a ...two-step in vitro enzymatic modification of glycoproteins, which has previously only been achieved by chemical means Gregoriadis G, Jain S, Papaioannou I, Laing Ρ (2005) Int J Pharm 300:125-130). This two-step procedure uses the Campylobacter jejuni Cst-ll α2,8-sialyltransferase to provide a primer on N-linked glycans, followed by polysialylation using the Neisseria meningitidis α2,8-polysialyltransferase. Here, we have demonstrated the ability of this system to modify three glycoproteins with varying N-linked glycan compositions: the human therapeutic proteins alpha-1-antitrypsin (A1AT) and factor IX, as well as bovine fetuin. The chain length of the polysialic acid addition was optimized by controlling reaction conditions. After demonstrating the ability of this system to modify a variety of proteins, the effect of polysialylation on the activity and serum half-life of A1AT was examined. The polysialylation of A1AT did not adversely affect its in vitro inhibition activity against human neutrophil elastase. The polysialylation of A1AT resulted in a significantly improved pharmacokinetic profile when the modified proteins were injected into CD-1 mice. Together, these results suggest that polysialylated A1AT may be useful for improved augmentation therapy for patients with a deficiency in this protein and that this modification may be applied to other therapeutic proteins.
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Abstract
Kohlenhydrate spielen eine wichtige Rolle bei biologischen Vorgängen. Das Fortschrittstempo der Kohlenhydratforschung ist jedoch relativ langsam, was unter anderem mit der Komplexität der ...Kohlenhydratstrukturen und dem Fehlen allgemein anwendbarer Synthesemethoden und Verfahren zur Untersuchung dieser Klasse von Biomolekülen zusammenhängt. Jüngste Fortschritte in der Synthese haben ergeben, dass viele dieser Probleme umgangen werden können. In diesem Aufsatz beschreiben wir die Methoden, die entwickelt wurden, um mit den Herausforderungen kohlenhydratvermittelter biologischer Vorgänge umzugehen. Besonderes Augenmerk wird dabei auf die Entwicklung der automatisierten Synthese von Oligosacchariden gerichtet. Darüber hinaus werden auch Kohlenhydrat‐Mikroarrays und Impfstoffe auf Kohlenhydratbasis behandelt.
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This method describes the use of subtilisin-catalyzed peptide condensation to form a 15-residue glycopeptide from two smaller synthetic peptides. A 12-residue peptide ester is synthesized by ...solid-phase peptide synthesis using a PAM-modified Rink amide resin that allows the formation of a peptide ester suitable for subtilisin ligation. The 12-residue acyl donor peptide ester is then ligated to a 3-residue acyl acceptor glycopeptide amide using subtilisin (EC 3.4.21.62) in a buffered mixture of water and DMF (1:9).
Impfung mit Zuckerle: Kapselsaccharide der N.‐meningitidis‐Serogruppe W135 wurden synthetisiert. Sera aus Mäusen, die mit diesen Konjugaten aus Di‐ bis Decasacchariden und Proteinen immunisiert ...worden waren, wurden mithilfe einer Glykan‐Mikroanordnung (siehe Bild) und in einem Bakterizidassay auf Antikörperspezifität und Wirkung gegen Bakterien getestet.
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This lecture will present our new development of methods and strategies to target the enzymes associated with carbohydrate synthesis and processing, with particular focus on the ...development of inhibitors and molecular probes associated with infectious diseases and cancer progression.
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Invariant natural killer T (iNKT) cells are an important source of both T helper type 1 (Th1) and Th2 cytokines, through which they can exert beneficial, as well as deleterious, effects in a variety ...of inflammatory diseases. This functional heterogeneity raises the question of how far phenotypically distinct subpopulations are responsible for such contrasting activities. In this study, we identify a particular set of iNKT cells that lack the NK1.1 marker (NK1.1neg) and secrete high amounts of interleukin (IL)-17 and low levels of interferon (IFN)-γ and IL-4. NK1.1neg iNKT cells produce IL-17 upon synthetic (α-galactosylceramide α-GalCer or PBS-57), as well as natural (lipopolysaccharides or glycolipids derived from Sphingomonas wittichii and Borrelia burgdorferi), ligand stimulation. NK1.1neg iNKT cells are more frequent in the lung, which is consistent with a role in the natural immunity to inhaled antigens. Indeed, airway neutrophilia induced by α-GalCer or lipopolysaccharide instillation was significantly reduced in iNKT-cell–deficient Jα18−/− mice, which produced significantly less IL-17 in their bronchoalveolar lavage fluid than wild-type controls. Furthermore, airway neutrophilia was abolished by a single treatment with neutralizing monoclonal antibody against IL-17 before α-GalCer administration. Collectively, our findings reveal that NK1.1neg iNKT lymphocytes represent a new population of IL-17–producing cells that can contribute to neutrophil recruitment through preferential IL-17 secretion.
Both five- and six-membered iminocyclitols have proven to be useful transition-state analogue inhibitors of glycosidases. They also mimic the transition-state sugar moiety of the nucleoside phosphate ...sugar in glycosyltransferase-catalyzed reactions. Described here is the development of a general strategy toward the parallel synthesis of a five-membered iminocyclitol linked to a hydroxamic acid group designed to mimic the transition state of GDP-fucose complexed with Mn(II) in fucosyltransferase reactions. The iminocyclitol 8 containing a protected hydroxylamine unit was prepared from d-mannitol. The hydroxamic acid moiety was introduced via the reaction of 8 with various acid chlorides. The strategy is generally applicable to the construction of libraries for identification of glycosyltransferase inhibitors.
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