Lipopeptides of the N-terminus of Escherichia coli lipoprotein: synthesis, mitogenicity and properties in monolayer experiments

Praß, Werner; Ringsdorf, Helmut; Bessler, Wolfgang G.; Wiesmüller, Karl‐Heinz; Jung, Günther

doi:10.1016/0005-2736(87)90283-5

Cited by 66 publications

(34 citation statements)

References 15 publications

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“…Lipopeptide 3, bearing a N -palmitoyllysine residue, was prepared using Fmoc- The two additional palmitoyl residues were introduced, still in solid phase, on the hydroxyl functions of the S-(2,3-dihydroxypropyl) present on the side chain of Cys, by recirculation of palmitoyl chloride, as previously described. 18,20 As control peptide, we synthesized Met-Ser-GpMBP(74-85) (4), elongating the wild-type sequence 1 with Met and Ser at the N-terminus.…”

Section: Resultsmentioning

confidence: 99%

Palmitoyl Derivatives of GpMBP Epitopes: T-Cell Response and Peptidases Susceptibility

Papini¹,

Mazzanti²,

Nardi³

et al. 2001

J. Med. Chem.

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We report for the first time the immunoadjuvant effects of lipoconjugation of peptide antigens in an in vitro system by using CD4+ T-cells. The lipopeptides obtained by conjugating a palmitoyl moiety at the N R -terminal of Gln 74 or at the -NH 2 of Lys 75 of GpMBP(74-85) induced increased T-cell responsiveness compared to the native nonlipidated peptide. On the other hand, lipoderivatives of GpMBP(82-98) did not increase the T-cell response, demonstrating that the superagonist inducing effect of lipoconjugation is epitope-specific. Digestion of the two native peptides with cathepsin D and L, both implicated in antigen processing, and with a complete lysosomal fraction of a EBV-transformed B cell line shows that GpMBP(74-85) is resistant to cellular proteases, while GpMBP(82-98) is easily digested by these enzymes. These results suggest that the first prerequisite for increasing the T-cell response by lipoconjugation is the stability of the native peptide to peptidases, providing an important insight into the understanding of the immunoadjuvant effect of lipoderivative antigens.

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Section: Resultsmentioning

confidence: 99%

Palmitoyl Derivatives of GpMBP Epitopes: T-Cell Response and Peptidases Susceptibility

Papini¹,

Mazzanti²,

Nardi³

et al. 2001

J. Med. Chem.

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“…The minimal structure for biological activity is the Cys-Ser lipodipeptide46 with the lipoaminoacid Cys-OH derivative being almost inactive;47 the remainder of the peptidic unit appears, in large part, not to be critical for activity since a variety of analogues of different lengths with different amino acid sequences were found to be equipotent 4648–50 The ( R )-configuration at the asymmetric glyceryl carbon confers maximum activity,30;51 and the threshold of the acyl chain length of the two ester-bound fatty acids is 8 carbons, with shorter acyl analogues being inactive 36.…”

Section: Introductionmentioning

confidence: 99%

Structure−Activity Relationships in Toll-like Receptor-2 Agonistic Diacylthioglycerol Lipopeptides

Malladi

et al. 2010

J. Med. Chem.

105

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The N-termini of bacterial lipoproteins are acylated with a (S)-(2,3-bisacyloxypropyl)cysteinyl residue. Lipopeptides derived from lipoproteins activate innate immune responses by engaging Toll-like receptor 2 (TLR2), and are highly immunostimulatory and yet without apparent toxicity in animal models. The lipopeptides may therefore be useful as potential immunotherapeutic agents. Previous structure-activity relationships in such lipopeptides have largely been obtained using murine cells and it is now clear that significant species-specific differences exist between human and murine TLR responses. We have examined in detail the role of the highly conserved Cys residue as well as the geometry and stereochemistry of the Cys-Ser dipeptide unit. (R)-diacylthioglycerol analogues are maximally active in reporter gene assays using human TLR2. The Cys-Ser dipeptide unit represents the minimal part-structure, but its stereochemistry was found not to be a critical determinant of activity. The thioether bridge between the diacyl and dipeptide units is crucial, and replacement by an oxoether bridge results in a dramatic decrease in activity.

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“…As far as the structural prerequisites for bioactivity of lipopeptides are concerned, it has been shown that tripalmitoyl-S-glyceryl-L-Cys-Ser-Lys-Lys-Lys-Lys (Pam 3 CSK 4 ) was highly active, whereas the natural dipeptide part of the outer membrane lipoprotein, tripalmitoyl-S-glyceryl-L-Cys-Ser (Pam 3 CS), only has a low activity (34,35). It is known for many amphiphilic molecules like phospholipids and glycolipids that physical parameters are strong determinants of biological activity.…”

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confidence: 99%

Physicochemical and Biological Analysis of Synthetic Bacterial Lipopeptides

Schromm

Howe

Ulmer

et al. 2007

Journal of Biological Chemistry

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The importance of the biological function and activity of lipoproteins from the outer or cytoplasmic membranes of Gram-positive and Gram-negative bacteria is being increasingly recognized. It is well established that they are like the endotoxins (lipopolysaccharide (LPS)), which are the main amphiphilic components of the outer membrane of Gramnegative bacteria, potent stimulants of the human innate immune system, and elicit a variety of proinflammatory immune responses. Investigations of synthetic lipopeptides corresponding to N-terminal partial structures of bacterial lipoproteins defined the chemical prerequisites for their biological activity and in particular the number and length of acyl chains and sequence of the peptide part. Here we present experimental data on the biophysical mechanisms underlying lipopeptide bioactivity. Investigation of selected synthetic diacylated and triacylated lipopeptides revealed that the geometry of these molecules (i.e. the molecular conformations and supramolecular aggregate structures) and the preference for membrane intercalation provide an explanation for the biological activities of the different lipopeptides. This refers in particular to the agonistic or antagonistic activity (i.e. their ability to induce cytokines in mononuclear cells or to block this activity, respectively). Biological activity of lipopeptides was hardly affected by the LPS-neutralizing antibiotic polymyxin B, and the biophysical interaction characteristics were found to be in sharp contrast to that of LPS with polymyxin B. The analytical data show that our concept of "endotoxic conformation," originally developed for LPS, can be applied also to the investigated lipopeptide and suggest that the molecular mechanisms of cell activation by amphiphilic molecules are governed by a general principle.

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Lipopeptides of the N-terminus of Escherichia coli lipoprotein: synthesis, mitogenicity and properties in monolayer experiments

Cited by 66 publications

References 15 publications

Palmitoyl Derivatives of GpMBP Epitopes: T-Cell Response and Peptidases Susceptibility

Palmitoyl Derivatives of GpMBP Epitopes: T-Cell Response and Peptidases Susceptibility

Structure−Activity Relationships in Toll-like Receptor-2 Agonistic Diacylthioglycerol Lipopeptides

Physicochemical and Biological Analysis of Synthetic Bacterial Lipopeptides

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