Synthetic <i>S</i>‐(2,3‐dihydroxypropyl)‐cysteinyl peptides derived from the N‐terminus of the cytochrome subunit of the photoreaction centre of <i>Rhodopseudomonas viridis</i> enhance murine splenocyte proliferation

Jw, Metzger; Ag, Beck-Sickinger; Loleit, Manuel; Eckert, Marianne; Wg, Bessler; Jung, Günther

doi:10.1002/psc.310010305

Cited by 43 publications

(43 citation statements)

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“…This may correlate with the finding that Pam2Cys is a more potent macrophage and splenocyte stimulator than Pam3Cys (22,24,25). In the present study, we found that insertion of two serine residues between the lipid moiety and the peptide sequence increased the potency of the resulting Pam2Cys-containing immunogens.…”

Section: Discussionsupporting

confidence: 87%

“…Pam2Cys, an analog of Pam3Cys that has been isolated from mycoplasma, has also been reported to be capable of activating macrophages and splenocytes (22,24,25). The ability to chemically synthesize vaccines provides opportunities to incorporate immunostimulatory lipids at various positions within immunogens, allowing the final structure to be tuned to give the best or most appropriate immune response.…”

Section: Discussionmentioning

confidence: 99%

“…Later studies also demonstrated that insertion of Ser-D-Ser instead of Ser-Ser markedly decreased immunogenicity (41). However, serine residues are absent in naturally occurring Pam2Cys-containing structures including macrophage-activating lipopeptide 2 (25) and the splenocytestimulating lipopeptides initially investigated (22). In this study, where lipid is attached to the N terminus, the two serine residues could be acting either as an inert spacer between the lipid and the peptide sequence or as an extension of the T helper cell epitope and perhaps modulating immunological activity.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to Pam3Cys, Pam2Cys has only two ester-bound palmitic acids and a free amino group, which leads to improved water solubility of Pam2Cys-peptide constructs compared with Pam3Cys-peptide constructs. It has also been reported that Pam2Cys is a more potent stimulator of splenocytes (22) and macrophages (24,25) than is Pam3Cys. The structural similarity of Pam2Cys to Pam3Cys and its enhanced macrophage-activating properties, as well as its less hydrophobic nature, indicate that Pam2Cys could also be used as a self-adjuvanting moiety.…”

Section: Highly Immunogenic and Totally Synthetic Lipopeptides Asmentioning

confidence: 92%

“…Tripalmitoyl-S-glyceryl cysteine (Pam3Cys) is a synthetic version of the N-terminal moiety of Braun's lipoprotein that spans the inner and outer membranes of Gram-negative bacteria and has been shown to be capable of stimulating virus-specific CTL responses against influenza virus-infected cells (21) and to elicit protective Abs against foot-and-mouth disease (17) when coupled to the appropriate synthetic epitopes. Recently dipalmitoyl-S-glyceryl cysteine (Pam2Cys), an analog of Pam3Cys, has been synthesized (22) and been shown to correspond to the lipid moiety of macrophage-activating lipopeptide 2 isolated from myoplasma that lack cell walls (23)(24)(25). In contrast to Pam3Cys, Pam2Cys has only two ester-bound palmitic acids and a free amino group, which leads to improved water solubility of Pam2Cys-peptide constructs compared with Pam3Cys-peptide constructs.…”

Section: Highly Immunogenic and Totally Synthetic Lipopeptides Asmentioning

confidence: 99%

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

Zeng

Ghosh

Lau

et al. 2002

The Journal of Immunology

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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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Highly Immunogenic and Totally Synthetic Lipopeptides Asmentioning

confidence: 92%

Section: Highly Immunogenic and Totally Synthetic Lipopeptides Asmentioning

confidence: 99%

See 3 more Smart Citations

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

Zeng

Ghosh

Lau

et al. 2002

The Journal of Immunology

179

188

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Differential recognition of structural details of bacterial lipopeptides by toll-like receptors

et al. 2002

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The question which detailed structures of bacterial modulins determine their relative biological activity and respective host cell receptors was examined with synthetic variants of mycoplasmal lipopeptides as model compounds, as well as recombinant outer surface protein A (OspA) of Borrelia burgdorferi and lipoteichoic acid. Mouse fibroblasts bearing genetic deletions of various toll-like receptors (TLR) were the indicator cells to study receptor requirements, primary macrophages served to measure dose response. The following results were obtained: (i) the TLR system discriminates between modulins with three and those with two long-chain fatty acids in their lipid moiety, in that lipopeptides with three fatty acids were recognized by TLR2, whereas those with two long-chain fatty acids and lipoteichoic acid required the additional cooperation with TLR6; (ii) substitution of the free N terminus of mycoplasmal lipopeptides with an acetyl or palmitoyl group decreased the specific activity; (iii) removal of one or both ester-bound fatty acids lowered the specific activity by five orders of magnitude or deleted biological activity; (iv) oxidation of the thioether group lowered the specific activity by at least four orders of magnitude. The implications of these findings for physiological inactivation of lipopeptides and host-bacteria interactions in general are discussed. Abbreviations: LTA: Lipoteichoic acid MALP-2: Macrophage-activating lipopeptide of 2 kDa MCP-1: Monocyte chemoattractant protein -1 MDP-OspA: Delipidated form of OspA Lip-OspA: Outer surface lipoprotein A TLR: Tolllike receptor

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Toll‐like receptor 6‐independent signaling by diacylated lipopeptides

et al. 2004

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Bacterial lipopeptides are strong immune modulators that activate early host responses after infection as well as initiating adjuvant effects on the adaptive immune system. These lipopeptides induce signaling in cells of the immune system through Toll-like receptor 2 (TLR2)-TLR1 or TLR2-TLR6 heteromers. So far it has been thought that triacylated lipopeptides, such as the synthetic N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteine (Pam3)-CSK4, signal through TLR2-TLR1 heteromers, whereas diacylated lipopeptides, like the macrophage-activating lipopeptide from Mycoplasma fermentans (MALP2) or S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteine (Pam2)-CGNNDESNISFKEK, induce signaling through TLR2-TLR6 heteromers. Using new synthetic lipopeptide derivatives we addressed the contribution of the lipid and, in particular, the peptide moieties with respect to TLR2 heteromer usage. In contrast to the current model of receptor usage, not only triacylated lipopeptides, but also diacylated lipopeptides like Pam2CSK4 and the elongated MALP2 analog Pam2CGNNDESNISFKEK-SK4 (MALP2-SK4) induced B lymphocyte proliferation and TNF-a secretion in macrophages in a TLR6-independent manner as determined with cells from TLR6-deficient mice. Our results indicate that both the lipid and the Nterminal peptides of lipoproteins contribute to the specificity of recognition by TLR2 heteromers and are responsible for the ligand-receptor interaction on host cells. IntroductionToll-like receptors (TLR) are prominent pattern-recognition receptors (PRR) of the innate immune system, recognizing various invading microorganisms through conserved molecular structures, so-called pathogenassociated molecular patterns (PAMP) [1]. The receptors differ from each other not only in ligand specificity but also in their expression pattern on different cells of the innate immune system. In addition, distinct TLR are able to address different sets of inflammatory target genes [2]. [3] to attain specificity for a given stimulus [4][5][6][7].LP have been described as strong immunostimulatory compounds initiating early innate host defense reactions in cells such as macrophages and epithelial cells [8,9]. In addition, they are potent polyclonal activators of murine B lymphocytes [10]. Signaling through TLR2-TLRx heteromers by LP leads to the formation of an active signaling complex that includes MyD88 and the IL-1R-associated kinase (IRAK) proteins, finally resulting in the nuclear translocation of NF-jB and subsequent cytokine production [11]. As a consequence TLR2-dependent signaling initiates a variety of host defense responses including the activation of the adaptive immune system [12][13][14].Among the TLR2-dependent PAMP, LP are primary candidates for analyzing the structural requirements for heteromer usage, for several reasons. Firstly, these molecules are available from various different bacterial species expressing different molecular structures. Secondly, the chemical synthesis of LP analogues provides a vast variety of chemically defined m...

show abstract

Synthetic S‐(2,3‐dihydroxypropyl)‐cysteinyl peptides derived from the N‐terminus of the cytochrome subunit of the photoreaction centre of Rhodopseudomonas viridis enhance murine splenocyte proliferation

Cited by 43 publications

References 20 publications

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

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

Differential recognition of structural details of bacterial lipopeptides by toll-like receptors

Toll‐like receptor 6‐independent signaling by diacylated lipopeptides

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