Synthesis of a New Template with a Built‐in Adjuvant and Its Use in Constructing Peptide Vaccine Candidates Through Polyoxime Chemistry

Zeng, Weiguang; Jackson, David C.; Rose, Keith

doi:10.1002/psc.51

Cited by 31 publications

(17 citation statements)

References 25 publications

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“…Synthetic peptides T (SFERFEIFPKE; a T-cell epitope from influenza virus hemagglutinin protein), B1 (IPNDLPRSTAVVHQLK RKH), B2 (RFILAHLQNNYSPNGNTN), B3 (VGAGVNNEYNRILVG), Ser-TGGB1 (SSFERFEIFPKEGGIPNDLPRSTAVVHQLKRKH), Ser-TGGB2 (SSFERFEIFPKEGGRFILAHLQNNYSPNGNTN), and Ser-TGGB3 (SSFER FEIFPKEGGVGAGVNNEYNRILVG) were made by solid-phase synthesis on a model 430A machine (Applied Biosystems) using the improved tert-butoxycarbonyl chemistry (32) and were purified by reversed-phase high-pressure liquid chromatography (HPLC) and analyzed by electrospray ionization mass spectrometry as previously described (31). The N-terminal Ser residues of the diepitopic peptides (peptides TGGB1-to -3) were oxidized with periodate and, for each one, a tetraoxime was formed between the resulting glyoxylyl peptides and a tetrabranched core, (NH 2 OCH 2 CO) 4 -Lys 2 -Lys-Ser-Ser-Lys(Pam 3 Cys)-(Lys) 4 -OH (26,42). Tetraoximes were purified by HPLC and characterized by electrospray mass spectrometry.…”

Section: Methodsmentioning

confidence: 99%

Antibodies against Thrombospondin-Related Anonymous Protein Do Not InhibitPlasmodiumSporozoite Infectivity In Vivo

Gantt¹,

Persson²,

Rose

et al. 2000

Infect Immun

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101

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Thrombospondin-related anonymous protein (TRAP), a candidate malaria vaccine antigen, is required for Plasmodium sporozoite gliding motility and cell invasion. For the first time, the ability of antibodies against TRAP to inhibit sporozoite infectivity in vivo is evaluated in detail. TRAP contains an A-domain, a wellcharacterized adhesive motif found in integrins. We modeled here a three-dimensional structure of the TRAP A-domain of Plasmodium yoelii and located regions surrounding the MIDAS (metal ion-dependent adhesion site), the presumed business end of the domain. Mice were immunized with constructs containing these Adomain regions but were not protected from sporozoite challenge. Furthermore, monoclonal and rabbit polyclonal antibodies against the A-domain, the conserved N terminus, and the repeat region of TRAP had no effect on the gliding motility or sporozoite infectivity to mice. TRAP is located in micronemes, secretory organelles of apicomplexan parasites. Accordingly, the antibodies tested here stained cytoplasmic TRAP brightly by immunofluorescence. However, very little TRAP could be detected on the surface of sporozoites. In contrast, a dramatic relocalization of TRAP onto the parasite surface occurred when sporozoites were treated with calcium ionophore. This likely mimics the release of TRAP from micronemes when a sporozoite contacts its target cell in vivo. Contact with hepatoma cells in culture also appeared to induce the release of TRAP onto the surface of sporozoites. If large amounts of TRAP are released in close proximity to its cellular receptor(s), effective competitive inhibition by antibodies may be difficult to achieve.

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Section: Methodsmentioning

confidence: 99%

Antibodies against Thrombospondin-Related Anonymous Protein Do Not InhibitPlasmodiumSporozoite Infectivity In Vivo

Gantt¹,

Persson²,

Rose

et al. 2000

Infect Immun

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101

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“…Pam3Cys was prepared according to the method described by Wiesmuller et al (28) and modified by Zeng et al (29). The synthesis of Pam2Cys was adapted from previously described methods (30,31); specifically, 3-bromo-propan-1,2-diol was used instead of 3-chloro-propan-1,2-diol, and centrifugation, not filtration, was used to recover the product.…”

Section: Synthesis Of Pam3cys and Pam2cysmentioning

confidence: 99%

“…Pam3Cys or Pam2Cys was then coupled to the exposed ⑀-amino group according to the procedure described previously (29). Briefly, a 2-fold excess of Pam3Cys or Pam2Cys, OЈbenzotriazole-N,N,NЈ,NЈ-tetramethyluronium-tetrafluoroborate, and 1-hydroxybenzotriazole was dissolved in DCM, and a 3-fold excess of diisopropylethylamine was added.…”

Section: Peptide Synthesismentioning

confidence: 99%

Highly Immunogenic and Totally Synthetic Lipopeptides as Self-Adjuvanting Immunocontraceptive Vaccines

Zeng

Ghosh

Lau

et al. 2002

The Journal of Immunology

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179

188

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In this study, we describe the synthesis of various lipopeptides based on the sequence of luteinizing hormone-releasing hormone (LHRH) and report on their abilities to induce Abs against this “self” hormone when inoculated into mice in the absence of additional adjuvant. The peptides consisted of a colinear CD4+ T helper cell epitope from the L chain of influenza virus hemagglutinin and LHRH, which has B cell epitopes but no T cell epitopes present in its sequence. Lipids were attached either at the N terminus or between the T cell epitope and LHRH, in the approximate center of the peptide. The lipopeptide constructs displayed different solubilities and immunological properties that depended not only on the lipid content but also on the position of attachment of the lipids. Some of these constructs were highly immunogenic, inducing high titers of Ab, which were capable of efficiently sterilizing female mice when administered in saline by s.c. or intranasal routes. The most effective vaccines were highly soluble, contained the dipalmitoyl-S-glyceryl cysteine moiety, and had this lipid attached at the center of the molecule. The relative ability of the lipopeptides to induce an Ab response in the absence of external adjuvant was reflected by their ability to up-regulate the surface expression of MHC class II molecules on immature dendritic cells. These results demonstrate that the composition and position within peptide vaccines of self-adjuvanting lipid groups can influence the ability to induce the maturation of dendritic cells and, in turn, the magnitude of the resulting Ab response.

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“…Indicator peptides for binding assays were biotinylated at the N-terminus during synthesis (Mimotopes, Melbourne, Australia). The 〈-gliadin 57-73 (QLQPFPQPELPYPQPQS) lipopeptide was synthesized using FMOC chemistry followed by coupling to S-[2,3-bis(palmitoyloxy)-propyl]-cysteine, as previously described (26).…”

Section: Methodsmentioning

confidence: 99%

“…Computer analysis was performed using the SYFPEITHI (34) and ProPred (35) programs to find similarities between the hLa epitope sequences and putative DR3 binding motifs. Probable DRB1*0301 binding registers for each of the DR3-restricted epitopes uncovered in this study were identified ( Figure 4A), indicating that the most conserved residue is the p4 position, consisting of an aspartic acid (hLa [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] , hLa 55-72 , hLa 151-168 , hLa 211-228 , hLa [241][242][243][244][245][246][247][248][249][250][251][252][253][254][255][256][257][258] , and hLa 313-330 ) or conservatively substituted glutamic acid (hLa [46][47][48][49][50][51][52][53][54] ), in 7 of 7 epitopes, followed by p1 (in 5 of 7 epitopes), p6 (in 4 of 7 epitopes), and p9 (in 3 of 7 epitopes).…”

Section: Enhancement Of the Reactivity Of A Weak Epitope In Dr3/dq2mentioning

confidence: 99%

T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the hLa class II haplotype DRB10301/DQB10201

Dudek¹,

Maier²,

Chen³

et al. 2007

Arthritis & Rheumatism

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Objective. T cells are implicated in the production of anti-La/SSB and anti-Ro/SSA autoantibodies commonly associated with the DR3/DQ2 haplotype in systemic lupus erythematosus and Sjögren's syndrome. This study was undertaken to investigate the DR3/DQ2-restricted T cell response to wild-type human La (hLa) and a truncated form of mutant La.Methods. Humanized transgenic mice expressing HLA-DRB1*0301/DQB1*0201 (DR3/DQ2) were immunized with recombinant antigen and examined for development of autoantibodies and T cell proliferation against overlapping peptides spanning the La autoantigen. HLA restriction and peptide binding of identified T cell epitopes to DR3 or DQ2 were determined using blocking monoclonal antibodies and a direct binding assay.Results. DR3/DQ2-transgenic mice generated an unusually rapid class-switched humoral response to hLa with characteristic spreading to Ro 52 and Ro 60 proteins following hLa protein immunization. Seven T cell determinants in hLa were restricted to the HLA-DR3/DQ2 haplotype. Six epitopes tested were restricted to HLA-DR and bound DR3 with semiconserved DR3 binding motifs. No DQ restriction of these epitopes was demonstrable despite efficient DQ binding activity in some cases. No neo-T cell epitopes were identified in mutant La; however, T cells primed with mutant La exhibited a striking increase in proliferation to the epitope hLa 151-168 compared with T cells primed with hLa.Conclusion. Multiple DR3-restricted epitopes of hLa have been identified. These findings suggest that truncation of La produced by somatic mutation or possibly granzyme B-mediated cleavage alters the immunodominance hierarchy of T cell responsiveness to hLa and may be a factor in the initiation or maintenance of anti-La autoimmunity.A striking feature of many rheumatic diseases is the development of antinuclear autoantibodies (ANAs) directed at selected nuclear components, including RNPs. These ANA specificities often occur as linked antibody sets recognizing different epitopes on the same macromolecular complex. La/SSB, a ubiquitous 49-kd RNP that binds several RNA polymerase IIItranscribed structural RNAs, exists in the nucleus as part of a complex with Ro/SSA and its associated yRNA molecules. Autoantibodies directed against La are a

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Synthesis of a New Template with a Built‐in Adjuvant and Its Use in Constructing Peptide Vaccine Candidates Through Polyoxime Chemistry

Cited by 31 publications

References 25 publications

Antibodies against Thrombospondin-Related Anonymous Protein Do Not InhibitPlasmodiumSporozoite Infectivity In Vivo

Antibodies against Thrombospondin-Related Anonymous Protein Do Not InhibitPlasmodiumSporozoite Infectivity In Vivo

Highly Immunogenic and Totally Synthetic Lipopeptides as Self-Adjuvanting Immunocontraceptive Vaccines

T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the hLa class II haplotype DRB10301/DQB10201

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Synthesis of a New Template with a Built‐in Adjuvant and Its Use in Constructing Peptide Vaccine Candidates Through Polyoxime Chemistry

Cited by 31 publications

References 25 publications

Antibodies against Thrombospondin-Related Anonymous Protein Do Not InhibitPlasmodiumSporozoite Infectivity In Vivo

Antibodies against Thrombospondin-Related Anonymous Protein Do Not InhibitPlasmodiumSporozoite Infectivity In Vivo

Highly Immunogenic and Totally Synthetic Lipopeptides as Self-Adjuvanting Immunocontraceptive Vaccines

T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the hLa class II haplotype DRB1*0301/DQB1*0201

Contact Info

Product

Resources

About

T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the hLa class II haplotype DRB10301/DQB10201