Synthesis and immunological study of α-2,9-oligosialic acid conjugates as anti-group C meningitis vaccines

Liao, Guochao; Zhou, Zhifang; Guo, Zhongwu

doi:10.1039/c5cc01794g

Cited by 46 publications

(49 citation statements)

References 49 publications

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“…The two methods afforded similar results of carbohydrate loading for 1b , 2b and 3b , that is, 12.1%, 15.2%, and 15.5% with MS and 9.8%, 15.1%, and 13.7% with the phenol-sulfuric acid method, respectively. Again this work confirmed that the results of sugar analysis obtained with the phenol-sulfuric acid method were reliable 32 and the method could be utilized to assess the carbohydrate loadings of the KLH conjugates 1a – 3a , whose molecular weights were too big for MS analysis. The conjugation of oligo-β-glucans with KLH was further verified with SDS-PAGE, which showed the increase in molecular mass of 1a – 3a as compared to KLH.…”

Section: Resultssupporting

confidence: 75%

“…This simple linker was selected since our previous studies proved that its conjugation reactions using activated glutaryl esters were easy and effective and it would not elicit antibodies against itself or affect the immunologic property of resultant glycoconjugates. 30–32 Consequently, 4–6 were treated with excessive disuccinimidyl glutarate (DSG, 15 eq.) in DMF to form activated monoesters 7–9 , which were readily purified via a precipitation process.…”

Section: Resultsmentioning

confidence: 99%

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6-O-Branched Oligo-β-glucan-Based Antifungal Glycoconjugate Vaccines

et al. 2015

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With the rapid growth in fungal infections and drug-resistant fungal strains, antifungal vaccines have become an especially attractive strategy to tackle this important health problem. β-Glucans, a class of extracellular carbohydrate antigens abundantly and consistently expressed on fungal cell surfaces, are intriguing epitopes for antifungal vaccine development. β-Glucans have a conserved β-1,3-glucan backbone with sporadic β-1,3- or β-1,6-linked short glucans as branches at the 6-O-positions, and the branches may play a critical role in their immunologic functions. To study the immunologic properties of branched β-glucans and develop β-glucan-based antifungal vaccines, three branched β-glucan oligosaccharides with 6-O-linked β-1,6-tetraglucose, β-1,3-diglucose, and β-1,3-tetraglucose branches on a β-1,3-nonaglucan backbone, which mimic the structural epitopes of natural β-glucans, were synthesized and coupled with keyhole limpet hemocyanin (KLH) to form novel synthetic conjugate vaccines. These glycoconjugates were proved to elicit strong IgG antibody responses in mice. It was also discovered that the number, size, and structure of branches linked to the β-glucan backbone had a significant impact on the immunologic property. Moreover, antibodies induced by the synthetic oligosaccharide-KLH conjugates were able to recognize and bind to natural β-glucans and fungal cells. Most importantly, these conjugates elicited effective protection against systemic Candida albicans infection in mice. Thus, branched oligo-β-glucans were identified as functional epitopes for antifungal vaccine design and the corresponding protein conjugates as promising antifungal vaccine candidates.

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Section: Resultssupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

6-O-Branched Oligo-β-glucan-Based Antifungal Glycoconjugate Vaccines

et al. 2015

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“…In the first approach, we envisionedadirect and highly convergent [2+ +2] assembly of Slinked disialyl donor 4 andl actose-derivedd isaccharide acceptor 6a reminiscent of an a(2!3) sialylation strategy.T he Slinked a(2!8) disialosides 4 and 5 could be prepared by ah ighly stereoselective anomeric S-alkylation reaction [26] between ah ighly reactive thiol (generated in situ from 7 or 8) and C8-iodide-activated acceptor 9 or 10.T he second approach involved stepwise union of aC 8-iodide-activated thiosialyl donor (11 or 12)w ith lactoside acceptor 6c to form trisaccharide 13.This strategy would permit us to exploit asimilar S-glycosidic bond-formingr eactionw ith Neu5Ac2 -thioacetate 8 [21] to form the a(2!8)-S-glycosidic bond by a[1+ +1+ +2] glycosylation ( Figure 2). To investigate stereoselective a-sialylation we used building blocks 9-15 modified by as et of carefully chosen N5- [40] and hydroxyl-protecting groups, such as trifluoroacetyl (TFA), [32,41] cyclic N5,O4-oxazolidinone, [42] and chloroacetyl (ClAc) [43] groups,a long with traditional thiosialosides 8 and 16.I na ddition, we also investigated sialyl donors with ad ifferent anomeric leaving group (e.g.,p hosphate 5), [44,45] as well as the effect of the solvent on the a-selective sialylation reaction. [42,46] Furthermore, different maskeda mines in the hydrophobic C6 spacer appended at the reducing terminus of 6 were installed for furtherc onjugation to ac arrierp rotein to avoid undesired side reactions during the synthesis.…”

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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“…Due to the importance of sialic acids in physiology and pathogenesis, researches are now targeting the potential of these compounds in the production of pharmaceuticals (Liao et al, 2015;Spence et al, 2015;Zhang et al, 2014;Byrne et al, 2007;Kiefel and von Itzstein, 2002). Unfortunately, extraction of sialic acids and its derivatives in adequate amounts from natural sources is very challenging.…”

Section: Sialicmentioning

confidence: 99%

Mini Review: Oxazolidinone and Other Sialic Acid C5 Modifications Over the Past Decade

Salmasan

2016

KIMIKA

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The potential of sialic acids as therapeutic agents has gradually been recognized due to its importance in the proper functioning of living systems, and likewise the virulence of several pathogens. However, synthesis of these compounds often result in poor yields and selectivities because of inherent characteristics associated with their structures. Use of various promoters, solvent systems and introduction of auxiliaries has since improved the outlook of chemical sialylation. Of these, attachment of various groups on C5 has notably resulted in improved α-selectivity. This mini review focuses on C5 structural modification of sialic acids over the past decade, most notably the oxazolidinone group protection.

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Synthesis and immunological study of α-2,9-oligosialic acid conjugates as anti-group C meningitis vaccines

Cited by 46 publications

References 49 publications

6-O-Branched Oligo-β-glucan-Based Antifungal Glycoconjugate Vaccines

6-O-Branched Oligo-β-glucan-Based Antifungal Glycoconjugate Vaccines

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

Mini Review: Oxazolidinone and Other Sialic Acid C5 Modifications Over the Past Decade

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