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Article ; Online: A Three Component Synthetic Vaccine Containing a β-Mannan T-Cell Peptide Epitope and a β-Glucan Dendritic Cell Ligand

David R. Bundle / Eugenia Paszkiewicz / Hassan R. H. Elsaidi / Satadru Sekhar Mandal / Susmita Sarkar

Molecules, Vol 23, Iss 8, p

2018 Volume 1961

Abstract: Glycoconjugates prepared from the capsular polysaccharide of several pathogenic bacteria and carrier proteins, such as CRM 197 or tetanus toxoid, have been one of the most successful public health measures to be implemented in the last quarter century. A ...

Abstract	Glycoconjugates prepared from the capsular polysaccharide of several pathogenic bacteria and carrier proteins, such as CRM 197 or tetanus toxoid, have been one of the most successful public health measures to be implemented in the last quarter century. A crucial element in the success of conjugate vaccines has been the recruitment of T-cell help and systematic induction of a secondary immune response. The seminal discovery, that degraded polysaccharide fragments with attached peptide are presented to the T-cell receptor of carbohydrate specific T-cells by MHC-II molecules that bind to the peptide component of degraded vaccine, suggests potentially novel designs for conjugate vaccines. A fully synthetic conjugate vaccine was constructed from a 1,2-linked β-mannose trisaccharide conjugated to a T-cell peptide, previously shown to afford protection against Candida albicans. This combined B- and T-cell epitope was synthesized with a C-terminal azidolysine residue for subsequent conjugation by click chemistry. Four copies of a β-1,3 linked hexaglucan dendritic cell epitope were conjugated to an asymmetric dendrimer bearing an alkyne terminated tether. Click chemistry of these two components created a conjugate vaccine that induced antibodies to all three epitopes of the fully synthetic construct.
Keywords	synthetic glycoconjugate vaccine ; glycopeptide B and T cell epitope ; β-glucan dendritic cell epitope ; dectin-1 targeting ; asymmetric dimeric dendrimer antigen ; antibody response ; Organic chemistry ; QD241-441
Subject code	540
Language	English
Publishing date	2018-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Tip of Brucella O-Polysaccharide Is a Potent Epitope in Response to Brucellosis Infection and Enables Short Synthetic Antigens to Be Superior Diagnostic Reagents

Lucy Duncombe / Laurence Howells / Anna Haughey / Andrew V. Taylor / Daryan Kaveh / Sevil Erdenliğ Gϋrbilek / Anne Dell / Paul G. Hitchen / Stuart M. Haslam / Satadru Sekhar Mandal / N. Vijaya Ganesh / David R. Bundle / John McGiven

Microorganisms, Vol 10, Iss 708, p

2022 Volume 708

Abstract: Brucellosis is a global disease and the world’s most prevalent zoonosis. All cases in livestock and most cases in humans are caused by members of the genus Brucella that possess a surface O-polysaccharide (OPS) comprised of a rare monosaccharide 4-deoxy- ... ...

Abstract	Brucellosis is a global disease and the world’s most prevalent zoonosis. All cases in livestock and most cases in humans are caused by members of the genus Brucella that possess a surface O-polysaccharide (OPS) comprised of a rare monosaccharide 4-deoxy-4-formamido-D-mannopyranose assembled with α1,2 and α1,3 linkages. The OPS of the bacterium is the basis for serodiagnostic tests for brucellosis. Bacteria that also contain the same rare monosaccharide can induce antibodies that cross-react in serological tests. In previous work we established that synthetic oligosaccharides, representing elements of the Brucella A and M polysaccharide structures, were excellent antigens to explore the antibody response in the context of infection, immunisation and cross reaction. These studies suggested the existence of antibodies that are specific to the tip of the Brucella OPS. Sera from naturally and experimentally Brucella abortus -infected cattle as well as from cattle experimentally infected with the cross-reactive bacterium Yersinia enterocolitica O:9 and field sera that cross react in conventional serological assays were studied here with an expanded panel of synthetic antigens. The addition of chemical features to synthetic antigens that block antibody binding to the tip of the OPS dramatically reduced their polyclonal antibody binding capability providing conclusive evidence that the OPS tip (non-reducing end) is a potent epitope. Selected short oligosaccharides, including those that were exclusively α1,2 linked, also demonstrated superior specificity when evaluated with cross reactive sera compared to native smooth lipopolysaccharide (sLPS) antigen and capped native OPS. This surprising discovery suggests that the OPS tip epitope, even though common to both Brucella and Y. enterocolitica O:9, has more specific diagnostic properties than the linear portion of the native antigens. This finding opens the way to the development of improved serological tests for brucellosis.
Keywords	Brucella ; O-polysaccharide ; epitope ; Biology (General) ; QH301-705.5
Subject code	540
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Synthesis of a 1,3 β-glucan hexasaccharide designed to target vaccines to the dendritic cell receptor, Dectin-1

Elsaidi, Hassan R.H / David R. Bundle / Eugenia Paszkiewicz

Carbohydrate research. 2015 May 18, v. 408

2015

Abstract: Transformation of 3-O-benzyl-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose into 2,4,6-tri-O-benzoyl-3-O-benzyl glucopyranosyl imidate proceeded efficiently via crystalline benzyl and per-benzoylated derivatives. This imidate glycosylated di-O- ... ...

Abstract	Transformation of 3-O-benzyl-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose into 2,4,6-tri-O-benzoyl-3-O-benzyl glucopyranosyl imidate proceeded efficiently via crystalline benzyl and per-benzoylated derivatives. This imidate glycosylated di-O-isopropylidene-α-d-glucofuranose in high yield and glycosylation of the disaccharide after removal of the 3′-O-benzyl ether afforded the β1,3 linked trisaccharide in excellent yield. Di- and trisaccharides imidates were readily prepared from the furanose terminated glycosylation products but both were unreactive in glycosylation reaction with the debenzylated di- and trisaccharide alcohols. The 3′-O-benzyl perbenzoylated disaccharide pyranose derivative could be selectively debenzoylated and converted to the corresponding perbenzoylated 4,6:4′,6′-di-O-benzylidene derivative. Lewis acid catalyzed glycosidation gave the selectively protected disaccharide ethylthioglycoside in good overall yield. Glycosidation of this thioglycoside donor with 5-methoxycarbonylpentanol gave the disaccharide tether glycoside and after catalytic removal of benzyl ether the resulting disaccharide alcohol was glycosylated by the thioglycoside in a 2+2 reaction to yield a tetrasaccharide. Repetition of selective deprotection of the terminal 3-O-benzyl ether followed by glycosylation by the disaccharide thioglycoside gave a protected hexasaccharide. Hydrogenolysis of this hexasaccharide followed by transesterification and second hydrogenolysis to remove a residual benzyl group gave the target hexasaccharide glycoside 1 as a Dectin-1 ligand functionalized to permit covalent attachment to glycoconjugate vaccines and thereby facilitate improved antigen processing by dendritic cells.
Keywords	alcohols ; antigens ; beta-glucans ; catalytic activity ; dendritic cells ; glycosides ; glycosylation ; imidoesters ; Lewis acids ; ligands ; moieties ; transesterification ; trisaccharides ; vaccines
Language	English
Dates of publication	2015-0518
Size	p. 96-106.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1435-7
ISSN	1873-426X ; 0008-6215
ISSN (online)	1873-426X
ISSN	0008-6215
DOI	10.1016/j.carres.2015.03.007
Database	NAL-Catalogue (AGRICOLA)

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Article: Synthesis of modified Trichinella spiralis disaccharide epitopes and a comparison of their recognition by chemical mapping and saturation transfer difference NMR

Cui, Lina / Chang-Chun Ling / David R. Bundle / Joanna Sadowska

Carbohydrate research. 2014 Jan. 13, v. 383

2014

Abstract: A rat monoclonal antibody 9D4 raised against the cell surface N-glycan of the parasite Trichinella spirallis protects rats against further infection. The terminal disaccharide β-d-Tyvp(1→3)β-d-GalNAcp (2) represents the immunodominant portion of the ... ...

Abstract	A rat monoclonal antibody 9D4 raised against the cell surface N-glycan of the parasite Trichinella spirallis protects rats against further infection. The terminal disaccharide β-d-Tyvp(1→3)β-d-GalNAcp (2) represents the immunodominant portion of the antigenic determinant. Chemical mapping of the antibody binding site by functional group modification employing monodeoxy and mono-O-methyl congeners identified key polar contacts and topography of the bound disaccharide. We report here a comparison of the chemical mapping studies with the antigen topography inferred from saturation transfer difference (STD) NMR experiments. During chemical mapping several congeners of compound 2 showed substantially enhanced binding. Pairing of these functional group modifications to create derivatives 6 and 7 did not show additive free energy gains and STD NMR data point to small variations in mode of binding as a probable cause. Improved syntheses of disaccharides 2–7 are reported.
Keywords	disaccharides ; epitopes ; Gibbs free energy ; moieties ; monoclonal antibodies ; nuclear magnetic resonance spectroscopy ; parasites ; rats ; Trichinella spiralis
Language	English
Dates of publication	2014-0113
Size	p. 1-13.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1435-7
ISSN	1873-426X ; 0008-6215
ISSN (online)	1873-426X
ISSN	0008-6215
DOI	10.1016/j.carres.2013.10.012
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Redesigning an Anti-Carbohydrate Antibody Specific for the Salmonella (Serotype B) O-Antigen

Saran A Narang, C Roger Mackenzie Su-Jun Deng, N Martin Young and David R Bundle

Proceedings of Indian National Science Academy, Vol 60, Iss 5B (2015)

2015

Abstract: Redesigning an Anti-Carbohydrate Antibody Specific for the Salmonella (Serotype B) O- ... ...

Abstract	Redesigning an Anti-Carbohydrate Antibody Specific for the Salmonella (Serotype B) O-Antigen
Keywords	Science ; Q
Language	English
Publishing date	2015-02-01T00:00:00Z
Publisher	Indian National Science Academy
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Synthesis of antifungal vaccines by conjugation of β-1,2 trimannosides with T-cell peptides and covalent anchoring of neoglycopeptide to tetanus toxoid

Cartmell, Jonathan / David R. Bundle / Eugenia Paszkiewicz / Pui-Hang Tam / Sebastian Dziadek / Susmita Sarkar / Thanh Luu / Tomasz Lipinski

Carbohydrate research. 2015 Feb. 11, v. 403

2015

Abstract: Selective strategies for the construction of novel three component glycoconjugate vaccines presenting Candida albicans cell wall glycan (β-1,2 mannoside) and polypeptide fragments on a tetanus toxoid carrier are described. The first of two conjugation ... ...

Abstract	Selective strategies for the construction of novel three component glycoconjugate vaccines presenting Candida albicans cell wall glycan (β-1,2 mannoside) and polypeptide fragments on a tetanus toxoid carrier are described. The first of two conjugation strategies employed peptides bearing an N-terminal thiopropionyl residue for conjugation to a trisaccharide equipped with an acrylate linker and a C-terminal S-acetyl thioglycolyl moiety for subsequent linking of neoglycopeptide to bromoacetylated tetanus toxoid. Michael addition of acrylate trisaccharides to peptide thiol under mildly basic conditions gave a mixture of N- and C- terminal glyco-peptide thioethers. An adaptation of this strategy coordinated S-acyl protection with anticipated thioester exchange equilibria. This furnished a single chemically defined fully synthetic neoglycopeptide conjugate that could be anchored to a tetanus toxoid carrier and avoids the introduction of exogenous antigenic groups. The second strategy retained the N-terminal thiopropionyl residue but replaced the C-terminal S-acetate functionality with an azido group that allowed efficient, selective formation of neoglycopeptide thioethers and subsequent conjugation of these with propargylated tetanus toxoid, but introduced potentially antigenic triazole linkages.
Keywords	Candida albicans ; cell walls ; chemical reactions ; moieties ; polypeptides ; tetanus ; thioesters ; thiols ; T-lymphocytes ; triazoles ; trisaccharides ; vaccines
Language	English
Dates of publication	2015-0211
Size	p. 123-134.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1435-7
ISSN	1873-426X ; 0008-6215
ISSN (online)	1873-426X
ISSN	0008-6215
DOI	10.1016/j.carres.2014.06.024
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Novel Solutions for Vaccines and Diagnostics To Combat Brucellosis

Satadru Sekhar Mandal / Lucy Duncombe / N. Vijaya Ganesh / Susmita Sarkar / Laurence Howells / Philip J. Hogarth / David R. Bundle / John McGiven

ACS Central Science, Vol 3, Iss 3, Pp 224-

2017 Volume 231

Keywords	Chemistry ; QD1-999
Language	English
Publishing date	2017-03-01T00:00:00Z
Publisher	American Chemical Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Self-adjuvanting glycopeptide conjugate vaccine against disseminated candidiasis.

Hong Xin / Jonathan Cartmell / Justin J Bailey / Sebastian Dziadek / David R Bundle / Jim E Cutler

PLoS ONE, Vol 7, Iss 4, p e

2012 Volume 35106

Abstract: Our research on pathogenesis of disseminated candidiasis led to the discovery that antibodies specific for Candida albicans cell surface β-1, 2-mannotriose [β-(Man)(3)] protect mice. A 14 mer peptide Fba, which derived from the N-terminal portion of the ... ...

Abstract	Our research on pathogenesis of disseminated candidiasis led to the discovery that antibodies specific for Candida albicans cell surface β-1, 2-mannotriose [β-(Man)(3)] protect mice. A 14 mer peptide Fba, which derived from the N-terminal portion of the C. albicans cytosolic/cell surface protein fructose-bisphosphate aldolase, was used as the glycan carrier and resulted in a novel synthetic glycopeptide vaccine β-(Man)(3)-Fba. By a dendritic cell-based immunization approach, this conjugate induced protective antibody responses against both the glycan and peptide parts of the vaccine. In this report, we modified the β-(Man)(3)-Fba conjugate by coupling it to tetanus toxoid (TT) in order to improve immunogenicity and allow for use of an adjuvant suitable for human use. By new immunization procedures entirely compatible with human use, the modified β-(Man)(3)-Fba-TT was administered either alone or as a mixture made with alum or monophosphoryl lipid A (MPL) adjuvants and given to mice by a subcutaneous (s.c.) route. Mice vaccinated with or, surprisingly, without adjuvant responded well by making robust antibody responses. The immunized groups showed a high degree of protection against a lethal challenge with C. albicans as evidenced by increased survival times and reduced kidney fungal burden as compared to control groups that received only adjuvant or DPBS buffer prior to challenge. To confirm that induced antibodies were protective, sera from mice immunized against the β-(Man)(3)-Fba-TT conjugate transferred protection against disseminated candidiasis to naïve mice, whereas C. albicans-absorbed immune sera did not. Similar antibody responses and protection induced by the β-(Man)(3)-Fba-TT vaccine was observed in inbred BALB/c and outbred Swiss Webster mice. We conclude that addition of TT to the glycopeptide conjugate results in a self-adjuvanting vaccine that promotes robust antibody responses without the need for additional adjuvant, which is novel and represents a major step forward in vaccine design against ...
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Impact of the Nature and Size of the Polymeric Backbone on the Ability of Heterobifunctional Ligands to Mediate Shiga Toxin and Serum Amyloid P Component Ternary Complex Formation

Glen D. Armstrong / George L. Mulvey / Thomas P. Griener / Ravin Narain / Zhicheng Deng / Marya Ahmed / Joanna M. Sadowska / Eugenia Paszkiewicz / Pavel I. Kitov / David R. Bundle

Toxins, Vol 3, Iss 9, Pp 1065-

2011 Volume 1088

Abstract: Inhibition of AB5-type bacterial toxins can be achieved by heterobifunctional ligands (BAITs) that mediate assembly of supramolecular complexes involving the toxin’s pentameric cell membrane-binding subunit and an endogenous protein, serum amyloid P ... ...

Abstract	Inhibition of AB5-type bacterial toxins can be achieved by heterobifunctional ligands (BAITs) that mediate assembly of supramolecular complexes involving the toxin’s pentameric cell membrane-binding subunit and an endogenous protein, serum amyloid P component, of the innate immune system. Effective in vivo protection from Shiga toxin Type 1 (Stx1) is achieved by polymer-bound, heterobifunctional inhibitors-adaptors (PolyBAITs), which exhibit prolonged half-life in circulation and by mediating formation of face-to-face SAP-AB5 complexes, block receptor recognition sites and redirect toxins to the spleen and liver for degradation. Direct correlation between solid-phase activity and protective dose of PolyBAITs both in the cytotoxicity assay and in vivo indicate that the mechanism of protection from intoxication is inhibition of toxin binding to the host cell membrane. The polymeric scaffold influences the activity not only by clustering active binding fragments but also by sterically interfering with the supramolecular complex assembly. Thus, inhibitors based on N-(2-hydroxypropyl) methacrylamide (HPMA) show significantly lower activity than polyacrylamide-based analogs. The detrimental steric effect can partially be alleviated by extending the length of the spacer, which separates pendant ligand from the backbone, as well as extending the spacer, which spans the distance between binding moieties within each heterobifunctional ligand. Herein we report that polymer size and payload of the active ligand had moderate effects on the inhibitor’s activity.
Keywords	E. coli O157:H7 ; multivalent inhibitors ; Pk-trisaccharide ; Gb3 ; Medicine ; R
Subject code	540
Language	English
Publishing date	2011-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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