ORCID Profile
0000-0002-9041-1852
Current Organisation
University of Nottingham
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Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6CC06010B
Abstract: A novel method for the introduction of a single protected amine-functional monomer at the chain end of RAFT polymers has been developed to enable native chemical ligation with peptide thioesters.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487442.V1
Abstract: Supplementary Data from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Chemical Society (ACS)
Date: 21-09-2018
DOI: 10.1021/JACS.8B07877
Abstract: Polyproline sequences are highly abundant in prokaryotic and eukaryotic proteins, where they serve as key components of secondary structure. To date, construction of the proline-proline motif has not been possible owing to steric congestion at the ligation junction, together with an n → π* electronic interaction that reduces the reactivity of acylated proline residues at the C-terminus of peptides. Here, we harness the enhanced reactivity of prolyl selenoesters and a trans-γ-selenoproline moiety to access the elusive proline-proline junction for the first time through a diselenide-selenoester ligation-deselenization manifold. The efficient nature of this chemistry is highlighted in the high-yielding one-pot assembly of two proline-rich polypeptide targets, submaxillary gland androgen regulated protein 3B and lumbricin-1. This method provides access to the most challenging of ligation junctions, thus enabling the construction of previously intractable peptide and protein targets of increasing structural complexity.
Publisher: Wiley
Date: 19-10-2020
Publisher: American Chemical Society (ACS)
Date: 26-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 11-03-2022
DOI: 10.1158/1078-0432.CCR-21-4283
Abstract: In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR lifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87 95% CI, 0.61–1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.
Publisher: Wiley
Date: 14-12-2016
Abstract: The use of native chemical ligation at selenocysteine (Sec) residues with peptide thioesters and additive-free selenocystine ligation with peptides bearing phenyl selenoesters, in concert with one-pot oxidative deselenization chemistry, is described. These approaches provide a simple and rapid method for accessing native peptides with serine in place of Sec at the ligation junction. The efficiency of both variants of the one-pot ligation-oxidative deselenization chemistry is probed through the synthesis of a MUC5AC-derived glycopeptide.
Publisher: Elsevier BV
Date: 2013
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532518.V1
Abstract: AbstractPurpose: In a i ost hoc /i analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with i IDH1/2 /i wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype ( i IDH /i -wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. Patients and Methods: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of i IDH1/2 /i wt and i H3F3A /i wt tumors with presence of i TERT /i promoter mutations and/or i EGFR /i lifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including i MGMT /i promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, i IDH /i -wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87 95% CI, 0.61–1.24). i MGMT /i promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. Conclusions: In this cohort of patients with glioblastoma, i IDH /i -wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of i MGMT /i promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population. /
Publisher: Wiley
Date: 26-04-2023
Abstract: Herein, we report the synthesis and characterization of a new class of hybrid Wells–Dawson polyoxometalate (POM) containing a diphosphoryl group (P 2 O 6 X) of the general formula [P 2 W 17 O 57 (P 2 O 6 X)] 6− (X=O, NH, or CR 1 R 2 ). Modifying the bridging unit X was found to impact the redox potentials of the POM. The ease with which a range of α‐functionalized diphosphonic acids (X=CR 1 R 2 ) can be prepared provides possibilities to access erse functionalized hybrid POMs. Compared to existing phosphonate hybrid Wells–Dawson POMs, diphosphoryl‐substituted POMs offer a wider tunable redox window and enhanced hydrolytic stability. This study provides a basis for the rational design and synthesis of next‐generation hybrid Wells–Dawson POMs.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487439
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Chemical Society (ACS)
Date: 18-07-2007
DOI: 10.1021/JA0689029
Abstract: We describe nanoscale protein pores modified with a single hyperbranched dendrimer molecule inside the channel lumen. Sulfhydryl-reactive polyamido amine (PAMAM) dendrimers of generations 2, 3 and 5 were synthesized, chemically characterized, and reacted with engineered cysteine residues in the transmembrane pore alpha-hemolysin. Successful coupling was monitored using an electrophoretic mobility shift assay. The results indicate that G2 and G3 but not G5 dendrimers permeated through the 2.9 nm cis entrance to couple inside the pore. The defined molecular weight cutoff for the passage of hyperbranched PAMAM polymers is in contrast to the less restricted accessibility of flexible linear poly(ethylene glycol) polymers of comparable hydrodynamic volume. Their higher compactness makes sulfhydryl-reactive PAMAM dendrimers promising research reagents to probe the structure of porous membrane proteins with wide internal diameters. The conductance properties of PAMAM-modified proteins pores were characterized with single-channel current recordings. A G3 dendrimer molecule in the channel lumen reduced the ionic current by 45%, indicating that the hyperbranched and positively charged polymer blocked the passage of ions through the pore. In line with expectations, a smaller and less dense G2 dendrimer led to a less pronounced current reduction of 25%. Comparisons to recordings of PEG-modified pores revealed striking dissimilarities, suggesting that differences in the structural dynamics of flexible linear polymers vs compact dendrimers can be observed at the single-molecule level. Current recordings also revealed that dendrimers functioned as ion-selectivity filters and molecular sieves for the controlled passage of molecules. The alteration of pore properties with charged and hyperbranched dendrimers is a new approach and might be extended to inorganic nanopores with applications in sensing and separation technology.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487424
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 13-08-2023
Abstract: ‘Bacterial‐type’ ferredoxins host a cubane [4Fe4S] 2+/+ cluster that enables these proteins to mediate electron transfer and facilitate a broad range of biological processes. Peptide maquettes based on the conserved cluster‐forming motif have previously been reported and used to model the ferredoxins. Herein we explore the integration of a [4Fe4S]‐peptide maquette into a H 2 ‐powered electron transport chain. While routinely formed under anaerobic conditions, we illustrate by electron paramagnetic resonance (EPR) analysis that these maquettes can be reconstituted under aerobic conditions by using photoactivated NADH to reduce the cluster at 240 K. Attempts to tune the redox properties of the iron‐sulfur cluster by introducing an Fe‐coordinating selenocysteine residue were also explored. To demonstrate the integration of these artificial metalloproteins into a semi‐synthetic electron transport chain, we utilize a ferredoxin‐inspired [4Fe4S]‐peptide maquette as the redox partner in the hydrogenase‐mediated oxidation of H 2 .
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487433.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487421
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487442
Abstract: Supplementary Data from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Chemical Society (ACS)
Date: 18-07-2023
Publisher: Wiley
Date: 09-07-2008
Publisher: Wiley
Date: 29-12-2008
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532518
Abstract: AbstractPurpose: In a i ost hoc /i analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with i IDH1/2 /i wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype ( i IDH /i -wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. Patients and Methods: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of i IDH1/2 /i wt and i H3F3A /i wt tumors with presence of i TERT /i promoter mutations and/or i EGFR /i lifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including i MGMT /i promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, i IDH /i -wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87 95% CI, 0.61–1.24). i MGMT /i promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. Conclusions: In this cohort of patients with glioblastoma, i IDH /i -wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of i MGMT /i promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487427.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 19-10-2020
Publisher: American Chemical Society (ACS)
Date: 10-07-2013
DOI: 10.1021/NL401968R
Abstract: The voltage-driven passage of biological polymers through nanoscale pores is an analytically, technologically, and biologically relevant process. Despite various studies on homopolymer translocation there are still several open questions on the fundamental aspects of pore transport. One of the most important unresolved issues revolves around the passage of biopolymers which vary in charge and volume along their sequence. Here we exploit an experimentally tunable system to disentangle and quantify electrostatic and steric factors. This new, fundamental framework facilitates the understanding of how complex biopolymers are transported through confined space and indicates how their translocation can be slowed down to enable future sensing methods.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487421.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Chemical Society (ACS)
Date: 09-08-2011
DOI: 10.1021/NN201705P
Abstract: Single-molecule characterization is essential for ascertaining the structural and functional properties of bottom-up DNA nanostructures. Here we enlist three atomic force microscopy (AFM) techniques to examine tetrahedron-shaped DNA nanostructures that are functionally enhanced with small chemical tags. In line with their application for biomolecule immobilization in biosensing and biophysics, the tetrahedra feature three disulfide-modified vertices to achieve directed attachment to gold surfaces. The remaining corner carries a single bioligand that can capture and present in idual cargo biomolecules at defined lateral nanoscale spacing. High-resolution AFM topographic imaging confirmed the directional surface attachment as well as the highly effective binding of in idual receptor molecules to the exposed bioligands. Insight into the binding behavior at the single-molecule level was gained using molecular recognition force spectroscopy using an AFM cantilever tip with a tethered molecular receptor. Finally, simultaneous topographic and recognition imaging demonstrated the specific receptor-ligand interactions on in idual tetrahedra. In summary, AFM characterization verified that the rationally designed DNA nanostructures feature characteristics to serve as valuable immobilization agents in biosensing, biophysics, and cell biology.
Publisher: Elsevier BV
Date: 05-2017
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487439.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 28-11-2013
DOI: 10.1002/PSC.2581
Abstract: The convergent assembly of peptide fragments by native chemical ligation has revolutionized the way in which proteins can be accessed by chemical synthesis. A variation of native chemical ligation involves the reaction of peptides bearing an N-terminal selenocysteine residue with peptide thioesters, which proceeds through the same mechanism as the parent reaction. This transformation was first investigated in 2001 for the installation of selenocysteine into peptides and proteins via ligation chemistry. The recent discovery that selenocysteine residues within peptides can be chemoselectively deselenized without the concomitant desulfurization of cysteine residues has led to renewed interest in ligation chemistry at selenocysteine. This review outlines the use of selenocysteine in ligation chemistry as well as recent investigations of chemoselective ligation-deselenization chemistry at other selenol-derived amino acids that have the potential to greatly expand the number of targets that can be accessed by chemical synthesis.
Publisher: Wiley
Date: 14-02-2023
Abstract: The site‐selective modification of peptides and proteins facilitates the preparation of targeted therapeutic agents and tools to interrogate biochemical pathways. Among the numerous bioconjugation techniques developed to install groups of interest, those that generate C(sp 3 )−C(sp 3 ) bonds are significantly underrepresented despite affording proteolytically stable, biogenic linkages. Herein, a visible‐light‐mediated reaction is described that enables the site‐selective modification of peptides and proteins via desulfurative C(sp 3 )−C(sp 3 ) bond formation. The reaction is rapid and high yielding in peptide systems, with comparable translation to proteins. Using this chemistry, a range of moieties is installed into model systems and an effective PTM‐mimic is successfully integrated into a recombinantly expressed histone.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487427
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487430.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 03-12-2021
Abstract: Post‐translational modifications (PTMs) enhance the repertoire of protein function and mediate or influence the activity of many cellular processes. The preparation of site‐specifically and homogeneously modified proteins, to apply as tools to understand the biological role of PTMs, is a challenging task. Herein, we describe a visible‐light‐mediated desulfurative C(sp 3 )–C(sp 3 ) bond forming reaction that enables the site‐selective installation of N ϵ ‐modified sidechains into peptides and proteins of interest. Rapid, operationally simple, and tolerant to ambient atmosphere, we demonstrate the installation of a range of lysine (Lys) PTMs into model peptide systems and showcase the potential of this technology by site‐selectively installing an N ϵ Ac sidechain into recombinantly expressed ubiquitin (Ub).
Publisher: Wiley
Date: 03-12-2021
Abstract: Post‐translational modifications (PTMs) enhance the repertoire of protein function and mediate or influence the activity of many cellular processes. The preparation of site‐specifically and homogeneously modified proteins, to apply as tools to understand the biological role of PTMs, is a challenging task. Herein, we describe a visible‐light‐mediated desulfurative C(sp 3 )–C(sp 3 ) bond forming reaction that enables the site‐selective installation of N ϵ ‐modified sidechains into peptides and proteins of interest. Rapid, operationally simple, and tolerant to ambient atmosphere, we demonstrate the installation of a range of lysine (Lys) PTMs into model peptide systems and showcase the potential of this technology by site‐selectively installing an N ϵ Ac sidechain into recombinantly expressed ubiquitin (Ub).
Publisher: Wiley
Date: 09-2015
Abstract: Despite the unique chemical properties of selenocysteine (Sec), ligation at Sec is an under-utilized methodology for protein synthesis. We describe herein an unprecedented protocol for the conversion of Sec to serine (Ser) in a single, high-yielding step. When coupled with ligation at Sec, this transformation provides a new approach to programmed ligations at Ser residues. This new reaction is compatible with a wide range of functionality, including the presence of unprotected amino acid side chains and appended glycans. The utility of the methodology is demonstrated in the rapid synthesis of complex glycopeptide fragments of the epithelial glycoproteins MUC5AC and MUC4 and through the total synthesis of the structured, cysteine (Cys)-free protein eglin C.
Publisher: Wiley
Date: 26-04-2023
Abstract: Herein, we report the synthesis and characterization of a new class of hybrid Wells–Dawson polyoxometalate (POM) containing a diphosphoryl group (P 2 O 6 X) of the general formula [P 2 W 17 O 57 (P 2 O 6 X)] 6− (X=O, NH, or CR 1 R 2 ). Modifying the bridging unit X was found to impact the redox potentials of the POM. The ease with which a range of α‐functionalized diphosphonic acids (X=CR 1 R 2 ) can be prepared provides possibilities to access erse functionalized hybrid POMs. Compared to existing phosphonate hybrid Wells–Dawson POMs, diphosphoryl‐substituted POMs offer a wider tunable redox window and enhanced hydrolytic stability. This study provides a basis for the rational design and synthesis of next‐generation hybrid Wells–Dawson POMs.
Publisher: American Chemical Society (ACS)
Date: 03-11-2015
DOI: 10.1021/JACS.5B07237
Abstract: We describe an unprecedented reaction between peptide selenoesters and peptide dimers bearing N-terminal selenocystine that proceeds in aqueous buffer to afford native amide bonds without the use of additives. The selenocystine-selenoester ligations are complete in minutes, even at sterically hindered junctions, and can be used in concert with one-pot deselenization chemistry. Various pathways for the transformation are proposed and probed through a combination of experimental and computational studies. Our new reaction manifold is also showcased in the total synthesis of two proteins.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487433
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487430
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487424.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Chemical Society (ACS)
Date: 14-05-2009
DOI: 10.1021/JA902004S
Abstract: The labeling of nucleotides and oligonucleotides with reporter groups is an important tool in the sequence-specific sensing of DNA, as exemplified by fluorescence tags. Here we show that chemical tags can encode sequence information for electrical nanopore recordings. In nanopore recordings, in idual DNA strands are electrophoretically driven through a nanoscale pore leading to detectable blockades of ionic current. The tags cause characteristic electrical signatures in the current blockades of translocating DNA strands and thereby encode sequence information. The viability of the strategy is demonstrated by discriminating between drug resistance-conferring point mutations. By being independent of pore engineering, the new approach can potentially enhance the sensing repertoire of durable solid-state nanopores for which alternative sensing strategies developed for protein pores are not easily accessible.
Publisher: Wiley
Date: 26-07-2010
Publisher: MDPI AG
Date: 08-12-2021
Abstract: Mucosal vaccination aims to prevent infection mainly by inducing secretory IgA (sIgA) antibody, which neutralises pathogens and enterotoxins by blocking their attachment to epithelial cells. We previously demonstrated that encapsulated protein antigen CD0873 given orally to hamsters induces neutralising antibodies locally as well as systemically, affording partial protection against Clostridioides difficile infection. The aim of this study was to determine whether displaying CD0873 on liposomes, mimicking native presentation, would drive a stronger antibody response. The recombinant form we previously tested resembles the naturally cleaved lipoprotein commencing with a cysteine but lacking lipid modification. A synthetic lipid (DHPPA-Mal) was designed for conjugation of this protein via its N-terminal cysteine to the maleimide headgroup. DHPPA-Mal was first formulated with liposomes to produce MalLipo then, CD0873 was conjugated to headgroups protruding from the outer envelope to generate CD0873-MalLipo. The immunogenicity of CD0873-MalLipo was compared to CD0873 in hamsters. Intestinal sIgA and CD0873-specific serum IgG were induced in all vaccinated animals however, neutralising activity was greatest for the CD0873-MalLipo group. Our data hold great promise for development of a novel oral vaccine platform driving intestinal and systemic immune responses.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Nicholas Mitchell.