Synthesis of Oligosaccharide-Polylysine Conjugates:  A Well Characterized Sialyl Lewis<sup>a</sup> Polymer for ELISA

Thoma, Gebhard; Magnani, John L.; Öhrlein, Reinhold; Ernst, Beat; Schwarzenbach, Franz; Duthaler, Rudolf O.

doi:10.1021/ja970657t

Cited by 44 publications

(28 citation statements)

References 20 publications

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“…Our poly-lysine based system, which had already been successfully applied for potent E-selectin ligands, [11] would be well-suited for a multivalent presentation of Linear-B. This scaffold has several advantages over many of the other approaches for multivalency.…”

Section: From Chemical Research To Industrial Applicationsmentioning

confidence: 99%

“…Commercially available poly-(l)-lysine hydrobromide batches 14 with average degree of polymerization n around 40, 250, or 1000 are then converted to the DMFsoluble per-chloroacetamides 15, which in turn are coupled with different equivalent amounts x of thiolated trisaccharide 16 as described previously. [11] The final Linear-B conjugates 17 are obtained by capping the remaining chloroacetamide groups with racemic thioglycerol. [15] The composition of these polymeric materials is given by the specification of the starting batch of 14 (vendor), and by 1 H-NMR measurements at elevated temperatures.…”

Section: + 11mentioning

confidence: 99%

“…[27] Under these circumstances the clinical development of GAS914 for eliminating xeno-antibodies was discontinued. It should, however, be noted, that the polylysine backbone of GAS914 [11,15] offers an excellent base for other antigen-specific therapies in antibody mediated diseases, be it as injectables or as ligands for immuneaphaeresis.…”

Section: Entrymentioning

confidence: 99%

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In vivo Neutralization of Naturally Existing Antibodies against Linear ?(1,3)-Galactosidic Carbohydrate Epitopes by Multivalent Antigen Presentation: A Solution for the First Hurdle of Pig-to-Human Xenotransplantation

Duthaler

Ernst

Fischer

et al. 2010

Chimia

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Pig-to-human xenotransplantation of islet cells or of vascularized organs would offer a welcome treatment alternative for the ever-increasing number of patients with end-stage organ failure who are waiting for a suitable allograph. The main hurdle are preexisting antibodies, most of which are specific for 'Linear-B', carbohydrate epitopes terminated by the unbranched Gal-?(1,3)Gal disaccharide. These antibodies are responsible for the 'hyper-acute rejection' of the xenograft by complement mediated hemorrhage. For depletion of such antibodies we have developed an artificial injectable antigen, a glycopolymer (GAS914) with a charge neutral poly-lysine backbone (degree of polymerization n = 1000) and 25% of its side chains coupled to Linear-B-trisaccharide. With an average molecular weight of 400 to 500 kD, presenting 250 trisaccharide epitopes per molecule, this multivalent array binds anti-?Gal antibodies with at least three orders of magnitude higher avidity on a per-saccharide basis than the monomeric epitope. In vivo experiments with non-human primates documented that rather low doses – 1 to 5 mg/kg of GAS914 injected i.v. – efficiently reduce the load of anti-Linear-B antibodies quickly by at least 80%. This treatment can be repeated without any sensitization to GAS914. Interestingly, although the antibody levels start raising 12 h after injection, they do not reach pretreatment levels. The polymer is degraded and excreted within hours, with a minute fraction remaining in lymphoid tissue of anti-?Gal producing animals only, probably binding to and inhibiting antibody-producing B-cells. The results of pig-to-non-human primate xenotransplantations established GAS914 as a relevant therapeutic option for pig-to-human transplantations as well. The synthesis of GAS914 was successfully scaled up to kg amounts needed for first clinical studies. Key was the use of galactosyl transferases and UDP-galactose for the synthesis of the trisaccharide.

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Section: From Chemical Research To Industrial Applicationsmentioning

confidence: 99%

Section: + 11mentioning

confidence: 99%

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In vivo Neutralization of Naturally Existing Antibodies against Linear ?(1,3)-Galactosidic Carbohydrate Epitopes by Multivalent Antigen Presentation: A Solution for the First Hurdle of Pig-to-Human Xenotransplantation

Duthaler

Ernst

Fischer

et al. 2010

Chimia

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“…Compounds 4 ± 7 were tested in a static, cell-free ligandbinding assay that measures E-selectin inhibition under equilibrium conditions [18]. To compare the data for different compounds obtained on different test plates, sLe x 1 (IC 50 1000 ± 1500 mm) was assayed on each plate as a reference.…”

mentioning

confidence: 99%

Simplified Sialyl Lewis^x Analogues with Improved E‐Selectin Inhibition

Thoma

Schwarzenbach

2003

Helvetica Chimica Acta

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The simplified sialyl Lewisx mimic 5 containing a D‐arabinose, a 3‐cyclohexyl‐2‐hydroxypropanoate, and a tetrahydropyran building block instead of L‐fucose, sialic acid, and N‐acetylglucosamine, respectively was synthesized. Compound 5 was 10‐fold more potent than sLex in a static E‐selectin binding assay and showed at 50 μM 75% inhibition in a dynamic‐flow assay in which sLex did not inhibit neutrophil rolling at up to 1000 μM. Compound 7 with a lactic acid instead of sialic acid building block showed threefold improved potency compared to sLex.

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“…In addition to the classical alkyne-azide coupling already mentioned, some further examples might be highlighted like the use of polymers containing pentafluorostyrene units for a thiol-p-fluoro 'click' glycosylation, [46] the attachment of thiolate oligosaccharides to chloroacetylated poly(L-lysine). [47] Catalytic chain transfer polymerization has been used to give alkyne-functional macromonomers that were subsequently functionalized with sugar azides and thiols using both Cu-catalyzed alkyne-azide coupling as well as thiol-ene Michael addition reactions. [48] Glycosylated block copolymers formed by a thiol-ene radical photoaddition reaction of 2,3,4,6-tetra-Oacetyl-1-thio-b-D-glucopyranose onto polybuta-1,2-diene-block-poly(ethylene oxide), which had been prepared by anionic polymerization, were demonstrated to spontaneously form vesicles (glycosomes) with asymmetric membranes with a sugar coating through self assembly in dilute aqueous solution (Scheme 3).…”

Section: Linear Glycopolymersmentioning

confidence: 99%

Glycopolymers of Various Architectures—More than Mimicking Nature

Voit

Appelhans

2010

Macro Chemistry & Physics

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Carbohydrates have a highly important role in biological functions. The increasing understanding of their biological interactions has also triggered a strongly increased interest in the preparation of synthetic glycopolymers of various architectures and well‐defined structure which can mimic biological functions in a less complex environment. In the last few years synthetic approaches in polymer science have been refined and newly developed in order to achieve complex carbohydrate architectures and to make use of them in various areas like glycomics, biotechnology, biosensors, and medicine. Besides the use of especially controlled radical polymerization techniques, highly efficient polymer analogous reactions that can be carried out in aqueous media have been developed and applied to linear and dendritic macromolecules. Self assembly aspects and their effectiveness in biological functions have been assessed.

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Synthesis of Oligosaccharide-Polylysine Conjugates: A Well Characterized Sialyl Lewis^a Polymer for ELISA

Cited by 44 publications

References 20 publications

In vivo Neutralization of Naturally Existing Antibodies against Linear ?(1,3)-Galactosidic Carbohydrate Epitopes by Multivalent Antigen Presentation: A Solution for the First Hurdle of Pig-to-Human Xenotransplantation

In vivo Neutralization of Naturally Existing Antibodies against Linear ?(1,3)-Galactosidic Carbohydrate Epitopes by Multivalent Antigen Presentation: A Solution for the First Hurdle of Pig-to-Human Xenotransplantation

Simplified Sialyl Lewis^x Analogues with Improved E‐Selectin Inhibition

Glycopolymers of Various Architectures—More than Mimicking Nature

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Synthesis of Oligosaccharide-Polylysine Conjugates: A Well Characterized Sialyl Lewisa Polymer for ELISA

Cited by 44 publications

References 20 publications

In vivo Neutralization of Naturally Existing Antibodies against Linear ?(1,3)-Galactosidic Carbohydrate Epitopes by Multivalent Antigen Presentation: A Solution for the First Hurdle of Pig-to-Human Xenotransplantation

In vivo Neutralization of Naturally Existing Antibodies against Linear ?(1,3)-Galactosidic Carbohydrate Epitopes by Multivalent Antigen Presentation: A Solution for the First Hurdle of Pig-to-Human Xenotransplantation

Simplified Sialyl Lewisx Analogues with Improved E‐Selectin Inhibition

Glycopolymers of Various Architectures—More than Mimicking Nature

Contact Info

Product

Resources

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Synthesis of Oligosaccharide-Polylysine Conjugates: A Well Characterized Sialyl Lewis^a Polymer for ELISA

Simplified Sialyl Lewis^x Analogues with Improved E‐Selectin Inhibition