Glycosyltransferase‐Catalyzed Synthesis of Thiooligosaccharides

Rich, Justin; Szpacenko, Adam; Palcic, Monica M.; Bundle, David R.

doi:10.1002/anie.200352606

Cited by 55 publications

(27 citation statements)

References 18 publications

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“…8)Neu5Acg lycosidicl inkages, respectively,t he stereoselective introduction of either molecule is difficult to achieve by chemical synthesis. Previous studies of glycosyltransferase-catalyzed glycosidicb ond formation with thiol-based acceptors, such as 3'-thiolactosides, showed promising resultsf or the synthesis of thiooligosaccharides, [39] but the generation of inter-S-glycosidic linkagesd uring S-linked GM3 synthesis was hampered [17] largely because of substrate intolerance.T hus, chemical synthesis is the most-promising route to prepare large quantities of Slinked carbohydrate antigens. The reactionisalso disfavored by the sterically crowded tertiary center of the anomeric Neu5AcC 2t hiolate moiety.A lthough chemoenzymatic methods that use glycosyltransferases are suitable for the large-scale productiono fG D3 and its derivatives, [35][36][37][38] this strategyi sn ot feasible for the analogous S-linkedG D3 tetrasaccharide.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of an S‐Linked α(2→8) GD3 Antigen and Evaluation of the Immunogenicity of Its Glycoconjugate

Kuan

Adak

et al. 2017

Chemistry A European J

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Replacing the interglycosidic oxygen atom of oligosaccharides with a nonhydrolyzable sulfur atom has attracted significant interest because it provides opportunities for developing new glycoconjugate vaccines. Herein, a stereocontrolled and highly convergent method to synthesize a non-reducing-end inter-S-glycosidic variant of the GD3 antigen (S-linked α(2→8) GD3) that is resistant to enzymatic hydrolysis is reported. The key steps in the synthesis are a regio- and stereoselective α(2→3) sialylation of a lactoside acceptor with a C8-iodide-derivatized sialyl donor and an anomeric S-alkylation, which enable stereoselective construction of a terminal S-linked α(2→8) disialyl residue. The sulfhydryl-reactive maleimide group was used as the linker for the well-defined conjugation of these antigens to the immunogenic protein keyhole limpet hemocyanin (KLH). Groups of mice were immunized with the GD3-KLH and S-linked GD3-KLH glycoconjugates in the presence of complete Freund's adjuvant. Microarray analysis of the sera showed the promise of the S-linked GD3-KLH vaccine: it stimulated a high immunoglobulin G response against S-linked GD3 and cross-reactivity with the O-linked GD3 antigen was low. The activity of the S-linked GD3-KLH vaccine was comparable to that of the O-linked GD3-KLH vaccine, which highlighted the effectiveness of generating glycoconjugate vaccines and immunotherapies by relatively simple means.

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Section: Resultsmentioning

confidence: 99%

Synthesis of an S‐Linked α(2→8) GD3 Antigen and Evaluation of the Immunogenicity of Its Glycoconjugate

Kuan

Adak

et al. 2017

Chemistry A European J

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“…A protecting group strategy was selected that would allow for a chemical synthesis of the S‐GM 2 tetrasaccharide from S‐GM 3 in the event that this approach was unsuccessful. Although we have recently demonstrated the use of carbohydrate thiols as acceptors in glycosyltransferase catalyzed glycosylations, 3′‐thiolactosides have proven unsuitable substrates for sialyltransferases that we have studied, necessitating a chemical synthesis of S‐GM 3 43. The protected trisaccharide 3 a was constructed via the coupling of the S‐GM 4 disaccharide 4 with glucoside 5 .…”

Section: Resultsmentioning

confidence: 99%

Chemical and Chemoenzymatic Synthesis of S‐Linked Ganglioside Analogues and Their Protein Conjugates for Use as Immunogens

Rich

Wakarchuk

Bundle

2006

Chemistry A European J

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Analogues of the tumor-associated gangliosides GM(3) and GM(2) containing terminal S-linked neuraminic acid residues and an amino terminated, truncated ceramide homologue have been synthesized and conjugated to a protein. The synthesis involved coupling of a S-linked sialyl alpha(2-->3) galactose disaccharide with a glucosyl sphingosine analogue, followed by elaboration and deprotection to give amino-terminated glycosyl ceramide 1. Glycosyltransferase-catalyzed extension of the trisaccharide 1 provided access to the modified GM(2) tetrasaccharide 2 or sulphur-containing GD(3) analogue 30. Owing to their potentially enhanced resistance to endogenous exo-glycoside hydrolases and their inherent non-self character, carbohydrate antigens containing non-reducing terminal thioglycosidic linkages may be more immunogenic than O-linked antigens and may stimulate the production of antibodies capable of recognizing naturally occurring oligosaccharides. Our initial results suggest that in fact these antigens are viable immunogens and furthermore, that immune sera cross reacts with O-gangliosides in the context of a heterologous glycoprotein conjugate.

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“…This requirement seems to be not so stringent for other GTs. For instance, thiooligosaccharides syntheses catalyzed by recombinant bovine a-1,3-GalT and by N. meningitides b-1,3-GlcNAcT in the presence of 3 0 -thiolactose as an acceptor have been described [158].…”

Section: Substrate Specificity and Synthetic Applicationsmentioning

confidence: 99%

Hydrolysis and Formation of Glycosidic Bonds

Monti

Riva

2012

Enzyme Catalysis in Organic Synthesis

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Carbohydrates play an important role in many biological events, such as cellular communication and physiological responses. In fact, oligosaccharides and various glycoconjugates have been shown to modulate different molecular recognition processes, including viral and bacterial pathogens recognition [1][2][3][4][5], tumor-associated cell adhesion and metastasis events [6-8], immune response [9], fertilization [10], and neuronal development [11]. This significant role, together with advances in the glycomics field and the recent developments of new synthetic methodologies, for example, the glycorandomization of biologically active natural products [12,13], makes glycoconjugates extremely attractive therapeutic targets nowadays [14][15][16][17].However, the presence of multiple functional groups and stereocenters in carbohydrates makes them challenging targets for organic chemists. Time-consuming protecting group manipulations and complex synthetic schemes are often required to suitably discriminate among hydroxyl groups with similar reactivities and/or to obtain the desired glycosidic linkage by using specifically activated donors and acceptors. Both regioselectivity and stereospecificity need to be strictly controlled and, as the number of different monosaccharide units as well as of glycan structures of interest is very large, a general methodology for oligosaccharide synthesis is still far from being reached. Moreover, despite recent progress in the solid-phase synthesis of oligosaccharides [14,16,18], an automated oligosaccharide synthesizer for all purposes is not yet commercially available and not all the common glycosidic linkages are accessible. Even the structural characterization of the saccharidic part of novel glycoconjugates from natural sources is still a demanding task -no automated sequencing techniques are fully developed, unlike the case of nucleic acids and peptides.Finally, the natural complexity of glycoconjugates is amplified by the extreme variety of aglycon structures coupled to the glycan chains, which can range from Enzyme Catalysis in Organic Synthesis, Third Edition. Edited

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Glycosyltransferase‐Catalyzed Synthesis of Thiooligosaccharides

Cited by 55 publications

References 18 publications

Synthesis of an S‐Linked α(2→8) GD3 Antigen and Evaluation of the Immunogenicity of Its Glycoconjugate

Synthesis of an S‐Linked α(2→8) GD3 Antigen and Evaluation of the Immunogenicity of Its Glycoconjugate

Chemical and Chemoenzymatic Synthesis of S‐Linked Ganglioside Analogues and Their Protein Conjugates for Use as Immunogens

Hydrolysis and Formation of Glycosidic Bonds

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