Abstract
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 Gram-negative 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.
Highlights
Beside lipopolysaccharides (LPS,2 endotoxin), which are the major amphiphilic components of the outer membrane of Gram-negative bacteria, other amphiphilic molecules such as lipoproteins and lipopeptides (LP) are found in the cell wall of a large number of microorganisms, including Gram-negative as well as Gram-positive bacteria, mycobacteria, mycoplasms, and spirochetes [1,2,3,4,5]
Synthetic Lipolanthionine Peptide Antagonizes Cell Activation by LPS—It was recently demonstrated that lipolan (Fig. 1) acts as an inhibitor of TLR2-mediated IL-8 secretion induced by the biologically active synthetic lipopeptide Pam3CSK4 [46]
Because we did not observe any biological activity of lipolan in human mononuclear cells, we investigated the antagonistic activity of this TLR2 inhibitor with respect to stimulation by LPS (Fig. 3)
Summary
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). 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 (Pam3CSK4) was highly active, whereas the natural dipeptide part of the outer membrane lipoprotein, tripalmitoyl-S-glyceryl-L-Cys-Ser (Pam3CS), 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. We present data showing that a biologically inactive lipopeptide, which antagonizes cell activation by biologically active lipopeptides, is able to antagonize cell activation by LPS, supporting the broad validity of the conformation concept for agonistic as well as antagonistic activity
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