The Experts below are selected from a list of 16338 Experts worldwide ranked by ideXlab platform
Shizuo Akira - One of the best experts on this subject based on the ideXlab platform.
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TLR1- and TLR6-independent recognition of bacterial Lipopeptides.
Journal of Biological Chemistry, 2006Co-Authors: Ute Buwitt-beckmann, Shizuo Akira, Holger Heine, Karl-heinz Wiesmüller, Günther Jung, Roland Brock, Artur J. UlmerAbstract:Bacterial cell walls contain lipoproteins/peptides, which are strong modulators of the innate immune system. Triacylated Lipopeptides are assumed to be recognized by TLR2/TLR1-, whereas diacylated Lipopeptides use TLR2/TLR6 heteromers for signaling. Following our initial discovery of TLR6-independent diacylated Lipopeptides, we could now characterize di- and triacylated Lipopeptides (e.g. Pam(2)C-SK(4), Pam(3)C-GNNDESNISFKEK), which have stimulatory activity in TLR1- and in TLR6-deficient mice. Furthermore, for the first time, we present triacylated Lipopeptides with short length ester-bound fatty acids (like PamOct(2)C-SSNASK(4)), which induce no response in TLR1-deficient cells. No differences in the phosphorylation of MAP kinases by Lipopeptide analogs having different TLR2-coreceptor usage were observed. Blocking experiments indicated that different TLR2 heteromers recognize their specific Lipopeptide ligands independently from each other. In summary, a triacylation pattern is necessary but not sufficient to render a Lipopeptide TLR1-dependent, and a diacylation pattern is necessary but not sufficient to render a Lipopeptide TLR6-dependent. Contrary to the current model, distinct Lipopeptides are recognized by TLR2 in a TLR1- and TLR6-independent manner.
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Toll-like receptor 6-independent signaling by diacylated Lipopeptides.
European Journal of Immunology, 2004Co-Authors: Ute Buwitt-beckmann, Shizuo Akira, Holger Heine, Karl-heinz Wiesmüller, Günther Jung, Roland Brock, Artur J. UlmerAbstract: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-α 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 N-terminal peptides of lipoproteins contribute to the specificity of recognition by TLR2 heteromers and are responsible for the ligand–receptor interaction on host cells.
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Recognition of Lipopeptides by Toll-like receptors:
Journal of Endotoxin Research, 2002Co-Authors: Kiyoshi Takeda, Osamu Takeuchi, Shizuo AkiraAbstract:Toll-like receptors (TLRs) recognize specific molecular patterns present only in micro-organisms and thereby activate innate immune cells. TLR2 is essential for the recognition of peptidoglycan and lipoprotein/Lipopeptides. Lipoprotein/Lipopeptides are observed in cell walls of a variety of micro-organisms. Host immune cells recognize the specific patterns of lipoprotein/Lipopeptides through the association of TLR2 with other TLRs. TLR1 and TLR6 are highly homologous to TLR2 in structure. TLR6-deficient mice showed an impaired response to mycoplasmal Lipopeptides that are diacylated, whereas TLR1-deficient mice were defective in their response to bacterial Lipopeptides that are triacylated. TLR2-deficient mice did not show any inflammatory response to either type of Lipopeptide. The functional association of TLR2 with TLR1 or TLR6 has been demonstrated. Thus, TLR1 and TLR6 are involved in the discrimination of a subtle difference between triacyl and diacyl Lipopeptides through interaction with TLR2.
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cutting edge role of toll like receptor 1 in mediating immune response to microbial lipoproteins
Journal of Immunology, 2002Co-Authors: Osamu Takeuchi, Z. Dong, Takao Horiuchi, Robert L Modlin, Shintaro Sato, Katsuaki Hoshino, Kiyoshi Takeda, Shizuo AkiraAbstract:The Toll-like receptor (TLR) family acts as pattern recognition receptors for pathogen-specific molecular patterns (PAMPs). TLR2 is essential for the signaling of a variety of PAMPs, including bacterial lipoprotein/Lipopeptides, peptidoglycan, and GPI anchors. TLR6 associates with TLR2 and recognizes diacylated mycoplasmal Lipopeptide along with TLR2. We report here that TLR1 associates with TLR2 and recognizes the native mycobacterial 19-kDa lipoprotein along with TLR2. Macrophages from TLR1-deficient (TLR1 −/− ) mice showed impaired proinflammatory cytokine production in response to the 19-kDa lipoprotein and a synthetic triacylated Lipopeptide. In contrast, TLR1 −/− cells responded normally to diacylated Lipopeptide. TLR1 interacts with TLR2 and coexpression of TLR1 and TLR2 enhanced the NF-κB activation in response to a synthetic Lipopeptide. Furthermore, lipoprotein analogs whose acylation was modified were preferentially recognized by TLR1. Taken together, TLR1 interacts with TLR2 to recognize the lipid configuration of the native mycobacterial lipoprotein as well as several triacylated Lipopeptides.
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discrimination of bacterial lipoproteins by toll like receptor 6
International Immunology, 2001Co-Authors: Osamu Takeuchi, Kiyoshi Takeda, Peter F Muhlradt, Taro Kawai, Michael Morr, Justin D Radolf, Arturo Zychlinsky, Shizuo AkiraAbstract:Bacterial lipoproteins (BLP) trigger immune responses via Toll-like receptor 2 (TLR2) and their immunostimulatory properties are attributed to the presence of a lipoylated N-terminus. Most BLP are triacylated at the N-terminus cysteine residue, but mycoplasmal macrophage-activating Lipopeptide-2 kD (MALP-2) is only diacylated. Here we show that TLR6-deficient (TLR6 –/– ) cells are unresponsive to MALP-2 but retain their normal responses to Lipopeptides of other bacterial origins. Reconstitution experiments in TLR2 –/– TLR6 –/– embryonic fibroblasts reveal that coexpression of TLR2 and TLR6 is absolutely required for MALP-2 responsiveness. Taken together, these results show that TLR6 recognizes MALP-2 cooperatively with TLR2, and appears to discriminate between the N-terminal lipoylated structures of MALP-2 and Lipopeptides derived from other bacteria.
Anthony B Nesburn - One of the best experts on this subject based on the ideXlab platform.
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Lipopeptide vaccines yesterday today and tomorrow
Lancet Infectious Diseases, 2002Co-Authors: Lbachir Benmohamed, Steven L Wechsler, Anthony B NesburnAbstract:Summary Peptide-based vaccines offer several potential advantages over the conventional whole proteins (or whole gene, in the case of genetic immunisation) in terms of purity and a high specificity in eliciting immune responses. However, concerns about toxic adjuvants, which are critical for immunogenicity of synthetic peptides, still remain. Lipopeptides, a form of peptide vaccine, discovered more then a decade ago, are currently under intensive investigation because they can generate comprehensive immune responses, without the use of adjuvants. In this review, we address the past of Lipopeptide vaccines, highlight the progress made toward their optimisation, and stress future challenges and issues related to their synthesis, formulation, and delivery. In particular, the recent development of mucosal application of Lipopeptide vaccines may present an ideal strategy against many pathogens that infect mucosal surfaces.
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Lipopeptide vaccines—yesterday, today, and tomorrow
Lancet Infectious Diseases, 2002Co-Authors: Lbachir Benmohamed, Steven L Wechsler, Anthony B NesburnAbstract:Summary Peptide-based vaccines offer several potential advantages over the conventional whole proteins (or whole gene, in the case of genetic immunisation) in terms of purity and a high specificity in eliciting immune responses. However, concerns about toxic adjuvants, which are critical for immunogenicity of synthetic peptides, still remain. Lipopeptides, a form of peptide vaccine, discovered more then a decade ago, are currently under intensive investigation because they can generate comprehensive immune responses, without the use of adjuvants. In this review, we address the past of Lipopeptide vaccines, highlight the progress made toward their optimisation, and stress future challenges and issues related to their synthesis, formulation, and delivery. In particular, the recent development of mucosal application of Lipopeptide vaccines may present an ideal strategy against many pathogens that infect mucosal surfaces.
Osamu Takeuchi - One of the best experts on this subject based on the ideXlab platform.
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Recognition of Lipopeptides by Toll-like receptors:
Journal of Endotoxin Research, 2002Co-Authors: Kiyoshi Takeda, Osamu Takeuchi, Shizuo AkiraAbstract:Toll-like receptors (TLRs) recognize specific molecular patterns present only in micro-organisms and thereby activate innate immune cells. TLR2 is essential for the recognition of peptidoglycan and lipoprotein/Lipopeptides. Lipoprotein/Lipopeptides are observed in cell walls of a variety of micro-organisms. Host immune cells recognize the specific patterns of lipoprotein/Lipopeptides through the association of TLR2 with other TLRs. TLR1 and TLR6 are highly homologous to TLR2 in structure. TLR6-deficient mice showed an impaired response to mycoplasmal Lipopeptides that are diacylated, whereas TLR1-deficient mice were defective in their response to bacterial Lipopeptides that are triacylated. TLR2-deficient mice did not show any inflammatory response to either type of Lipopeptide. The functional association of TLR2 with TLR1 or TLR6 has been demonstrated. Thus, TLR1 and TLR6 are involved in the discrimination of a subtle difference between triacyl and diacyl Lipopeptides through interaction with TLR2.
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cutting edge role of toll like receptor 1 in mediating immune response to microbial lipoproteins
Journal of Immunology, 2002Co-Authors: Osamu Takeuchi, Z. Dong, Takao Horiuchi, Robert L Modlin, Shintaro Sato, Katsuaki Hoshino, Kiyoshi Takeda, Shizuo AkiraAbstract:The Toll-like receptor (TLR) family acts as pattern recognition receptors for pathogen-specific molecular patterns (PAMPs). TLR2 is essential for the signaling of a variety of PAMPs, including bacterial lipoprotein/Lipopeptides, peptidoglycan, and GPI anchors. TLR6 associates with TLR2 and recognizes diacylated mycoplasmal Lipopeptide along with TLR2. We report here that TLR1 associates with TLR2 and recognizes the native mycobacterial 19-kDa lipoprotein along with TLR2. Macrophages from TLR1-deficient (TLR1 −/− ) mice showed impaired proinflammatory cytokine production in response to the 19-kDa lipoprotein and a synthetic triacylated Lipopeptide. In contrast, TLR1 −/− cells responded normally to diacylated Lipopeptide. TLR1 interacts with TLR2 and coexpression of TLR1 and TLR2 enhanced the NF-κB activation in response to a synthetic Lipopeptide. Furthermore, lipoprotein analogs whose acylation was modified were preferentially recognized by TLR1. Taken together, TLR1 interacts with TLR2 to recognize the lipid configuration of the native mycobacterial lipoprotein as well as several triacylated Lipopeptides.
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discrimination of bacterial lipoproteins by toll like receptor 6
International Immunology, 2001Co-Authors: Osamu Takeuchi, Kiyoshi Takeda, Peter F Muhlradt, Taro Kawai, Michael Morr, Justin D Radolf, Arturo Zychlinsky, Shizuo AkiraAbstract:Bacterial lipoproteins (BLP) trigger immune responses via Toll-like receptor 2 (TLR2) and their immunostimulatory properties are attributed to the presence of a lipoylated N-terminus. Most BLP are triacylated at the N-terminus cysteine residue, but mycoplasmal macrophage-activating Lipopeptide-2 kD (MALP-2) is only diacylated. Here we show that TLR6-deficient (TLR6 –/– ) cells are unresponsive to MALP-2 but retain their normal responses to Lipopeptides of other bacterial origins. Reconstitution experiments in TLR2 –/– TLR6 –/– embryonic fibroblasts reveal that coexpression of TLR2 and TLR6 is absolutely required for MALP-2 responsiveness. Taken together, these results show that TLR6 recognizes MALP-2 cooperatively with TLR2, and appears to discriminate between the N-terminal lipoylated structures of MALP-2 and Lipopeptides derived from other bacteria.
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cutting edge preferentially the r stereoisomer of the mycoplasmal Lipopeptide macrophage activating Lipopeptide 2 activates immune cells through a toll like receptor 2 and myd88 dependent signaling pathway
Journal of Immunology, 2000Co-Authors: Osamu Takeuchi, Katsuaki Hoshino, Peter F Muhlradt, Andreas Kaufmann, Karsten Grote, Taro Kawai, Michael Morr, Shizuo AkiraAbstract:Mycoplasmas and their membranes are potent activators of macrophages, the active principle being lipoproteins and Lipopeptides. Two stereoisomers of the mycoplasmal Lipopeptide macrophage-activating Lipopeptide-2 (MALP-2) differing in the configuration of the lipid moiety were synthesized and compared in their macrophage-activating potential, the R- MALP being >100 times more active than the S- MALP in stimulating the release of cytokines, chemokines, and NO. To assess the role of the Toll-like receptor (TLR) family in mycoplasmal Lipopeptide signaling, the MALP-2-mediated responses were analyzed using macrophages from wild-type, TLR2-, TLR4-, and MyD88-deficient mice. TLR2- and MyD88-deficient cells showed severely impaired cytokine productions in response to R- and S- MALP. The MALP-induced activation of intracellular signaling molecules was fully dependent on both TLR2 and MyD88. There was a strong preference for the R- MALP in the recognition by its functional receptor, TLR2.
Philippe Jacques - One of the best experts on this subject based on the ideXlab platform.
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Lipopeptide biodiversity in antifungal Bacillus strains isolated from Algeria
Archives of Microbiology, 2018Co-Authors: Lamia Abdellaziz, Max Béchet, Gabrielle Chataigné, Valérie Leclère, Marlène Chollet, Ahmed Abderrahmani, Lamia Yaici, Anthony Arguelles Arias, Philippe JacquesAbstract:Several Bacillus strains have been well studied for their ability to control soil-borne plant diseases. This property is linked to the production of several families of Lipopeptides. Depending of their structure, these compounds show antifungal and/or plant systemic resistance inducing activities. In this work, the biodiversity of Lipopeptides produced by different antifungal Bacillus strains isolated from seeds, rhizospheric, and non-rhizospheric soils in Algeria was analyzed. Sixteen active strains were characterized by PCR for their content in genes involved in Lipopeptide biosynthesis and by MALDI-ToF for their Lipopeptide production, revealing a high biodiversity of products. The difficulty to detect kurstakin genes led us to design two new sets of specific primers. An interesting potential of antifungal activity and the synthesis of two forms of fengycins differing in the eighth amino acid (Gln/Glu) were found from the strain 8. Investigation of its genome led to the finding of an adenylation domain of the fengycin synthetase predicted to activate the glutamate residue instead of the glutamine one. According to the comparison of both the results of MALDI-ToF-MS and genome analysis, it was concluded that this adenylation domain could activate both residues at the same time. This study highlighted that the richness of the Algerian ecosystems in Bacillus strains is able to produce: surfactin, pumilacidin, lichenysin, kurstakin, and different types of fengycins.
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Bioinformatics tools for the discovery of new Lipopeptides with biocontrol applications
European Journal of Plant Pathology, 2018Co-Authors: Maude Pupin, Philippe Jacques, Areski Flissi, Valérie LeclèreAbstract:As conventional or chemical pesticides have negative impact on environment and health of both farmer and consumers, it becomes relevant to develop alternative solutions to limit their use. In this context, innovative strategies to accelerate the development of biocontrol agents are welcome. For a decade of years, it has been demonstrated that Lipopeptides are very efficient weapons against fungi responsible for crop diseases. Lipopeptides are secondary metabolites, produced by many microorganisms including beneficial rhizobacteria. The Lipopeptide biosynthetic pathways include nonribosomal peptide synthetases. These modular enzymatic complexes work as assembly lines to build the peptides step by step, leading to the production of original peptide compounds with specific features as the presence of non proteinogenic monomers and cyclic and branched structures. In this paper, Florine and Norine bioinformatics tools, especially dedicated to non-ribosomal synthetases and their products are presented. Their use is mainly focused on the discovery of Lipopeptides produced by Bacillus or Pseudomonas because they seem to represent a versatile reservoir of active secondary metabolites with promising activities for applications in phytosanitary area.
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burkholderia genome mining for nonribosomal peptide synthetases reveals a great potential for novel siderophores and Lipopeptides synthesis
arXiv: Quantitative Methods, 2016Co-Authors: Qassim Esmaeel, Gabrielle Chataigné, M Bechet, Maude Pupin, Nam Phuong Kieu, Jovana Deravel, F Krier, Monica Hofte, Philippe JacquesAbstract:Burkholderia is an important genus encompassing a variety of species, including pathogenic strains as well as strains that promote plant growth. We have carried out a global strategy, which combined two complementary approaches. The first one is genome guided with deep analysis of genome sequences and the second one is assay guided with experiments to support the predictions obtained in silico. This efficient screening for new secondary metabolites, performed on 48 gapless genomes of Burkholderia species, revealed a total of 161 clusters containing nonribosomal peptide synthetases (NRPSs), with the potential to synthesize at least 11 novel products. Most of them are siderophores or Lipopeptides, two classes of products with potential application in biocontrol. The strategy led to the identification, for the first time, of the cluster for cepaciachelin biosynthesis in the genome of Burkholderia ambifaria AMMD and a cluster corresponding to a new malleobactin-like siderophore, called phymabactin, was identified in Burkholderia phymatum STM815 genome. In both cases, the siderophore was produced when the strain was grown in iron-limited conditions. Elsewhere, the cluster for the antifungal burkholdin was detected in the genome of B. ambifaria AMMD and also Burkholderia sp. KJ006. Burkholderia pseudomallei strains harbor the genetic potential to produce a novel Lipopeptide called burkhomycin, containing a peptidyl moiety of 12 monomers. A mixture of Lipopeptides produced by Burkholderia rhizoxinica lowered the surface tension of the supernatant from 70 to 27 mN·m−1. The production of nonribosomal secondary metabolites seems related to the three phylogenetic groups obtained from 16S rRNA sequences. Moreover, the genome-mining approach gave new insights into the nonribosomal synthesis exemplified by the identification of dual C/E domains in Lipopeptide NRPSs, up to now essentially found in Pseudomonas strains.
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Identification and biochemical characteristics of Lipopeptides from Bacillus mojavensis A21
Process Biochemistry, 2014Co-Authors: Hanen Ben Ayed, Philippe Jacques, Noomen Hmidet, Max Béchet, M. Chollet, Gabrielle Chataigné, Valérie Leclère, Moncef NasriAbstract:Abstract This study reports the potential of a marine bacterium, Bacillus mojavensis A21, to produce Lipopeptide biosurfactants. The crude Lipopeptide mixture was found to be very effective in reducing surface tension to 31 mN m −1 . PCR experiments using degenerate primers revealed the presence of nonribosomal peptide synthetases genes implied in the biosyntheses of fengycin and surfactin. Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF-MS) performed on whole cells of B. mojavensis A21 confirmed the presence of Lipopeptides identified as members of surfactin and fengycin families. Further, a detailed analysis performed by MALDI-TOF-TOF revealed the presence of pumilacidin compounds. The crude Lipopeptide mixture was tested for its inhibitory activity against Gram-positive and Gram-negative bacteria, and fungal strains. It was found to display significant antimicrobial activity. Strain A21 Lipopeptide mixture was insensitive to proteolytic enzymes, stable between pH 3.0 and 11.0, and resistant to high temperature. Production of Lipopeptides is a characteristic of several Bacillus species, but to our knowledge this is the first report involving identification of pumilacidin, surfactin and fengycin isoforms in a B. mojavensis strain.
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surfactin and other Lipopeptides from bacillus spp
2011Co-Authors: Philippe JacquesAbstract:Isolated during 1950s and 1960s, the group of Lipopeptides from Bacillus spp. gather more than 30 different peptides linked to various fatty acid chains. More than a 100 different compounds can so be described. In this chapter, they are classified into four main families: the surfactins, the iturins, the fengycins or plipastatins and the kurstakins. The biochemical mechanism responsible for their biosynthesis, which involved nonribosomal peptide synthetases, is described in detail. The complex cascade of regulation of surfactin synthetase operon and the environmental factors, which influence the Lipopeptide production, are discussed. The main physico-chemical properties of these remarkable biosurfactants and their possible relationships with the biological activities are also presented. A brief overview of the molecular strategies developed to get modified Lipopeptide compounds and the last bioprocesses set up for their production are given. In the last chapter, the main applications of surfactin are proposed.
Lbachir Benmohamed - One of the best experts on this subject based on the ideXlab platform.
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Lipopeptide vaccines yesterday today and tomorrow
Lancet Infectious Diseases, 2002Co-Authors: Lbachir Benmohamed, Steven L Wechsler, Anthony B NesburnAbstract:Summary Peptide-based vaccines offer several potential advantages over the conventional whole proteins (or whole gene, in the case of genetic immunisation) in terms of purity and a high specificity in eliciting immune responses. However, concerns about toxic adjuvants, which are critical for immunogenicity of synthetic peptides, still remain. Lipopeptides, a form of peptide vaccine, discovered more then a decade ago, are currently under intensive investigation because they can generate comprehensive immune responses, without the use of adjuvants. In this review, we address the past of Lipopeptide vaccines, highlight the progress made toward their optimisation, and stress future challenges and issues related to their synthesis, formulation, and delivery. In particular, the recent development of mucosal application of Lipopeptide vaccines may present an ideal strategy against many pathogens that infect mucosal surfaces.
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Lipopeptide vaccines—yesterday, today, and tomorrow
Lancet Infectious Diseases, 2002Co-Authors: Lbachir Benmohamed, Steven L Wechsler, Anthony B NesburnAbstract:Summary Peptide-based vaccines offer several potential advantages over the conventional whole proteins (or whole gene, in the case of genetic immunisation) in terms of purity and a high specificity in eliciting immune responses. However, concerns about toxic adjuvants, which are critical for immunogenicity of synthetic peptides, still remain. Lipopeptides, a form of peptide vaccine, discovered more then a decade ago, are currently under intensive investigation because they can generate comprehensive immune responses, without the use of adjuvants. In this review, we address the past of Lipopeptide vaccines, highlight the progress made toward their optimisation, and stress future challenges and issues related to their synthesis, formulation, and delivery. In particular, the recent development of mucosal application of Lipopeptide vaccines may present an ideal strategy against many pathogens that infect mucosal surfaces.
