The Chemical Synthesis of Cecropin D and an Analog with Enhanced Antibacterial Activity

Fink, J; Merrifield, R. B.; Boman, Anita; Boman, Hans G.

doi:10.1016/s0021-9258(18)83342-7

Cited by 63 publications

(10 citation statements)

References 31 publications

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“…A further aspect to be investigated is the role that the electrostatic interaction between the peptide and the membrane plays in the permeabilization process. For cryptdins [50] and cecropins [51], a direct correlation between cationic character and antimicrobial activity has been established. In the present case, loss of one positive charge in the N-acetyl-CA(1-8)M(1-18) produced a sharp decrease (50 %) in leishmanicidal activity.…”

Section: Discussionmentioning

confidence: 99%

The plasma membrane of Leishmania donovani promastigotes is the main target for CA(1–8)M(1–18), a synthetic cecropin A–melittin hybrid peptide

Díaz‐Achirica

Ubach

Guinea

et al. 1998

Biochemical Journal

102

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Reports on the lethal activity of animal antibiotic peptides have largely focused on bacterial rather than eukaryotic targets. In these, involvement of internal organelles as well as mechanisms different from those of prokaryotic cells have been described. CA(1-8)M(1-18) is a synthetic cecropin A-melittin hybrid peptide with leishmanicidal activity. Using Leishmania donovani promastigotes as a model system we have studied the mechanism of action of CA(1-8)M(1-18), its two parental peptides and two analogues. At micromolar concentration CA(1-8)M(1-18) induces a fast permeability to H+/OH-, collapse of membrane potential and morphological damage to the plasma membrane. Effects on other organelles are related to the loss of internal homeostasis of the parasite rather than to a direct effect of the peptide. Despite the fast kinetics of the process, the parasite is able to deactivate in part the effect of the peptide, as shown by the higher activity of the d-enantiomer of CA(1-8)M(1-18). Electrostatic interaction between the peptide and the promastigote membrane, the first event in the lethal sequence, is inhibited by polyanionic polysaccharides, including its own lipophosphoglycan. Thus, in common with bacteria, the action of CA(1-8)M(1-18) on Leishmania promastigotes has the same plasma membrane as target, but is unique in that different peptides show patterns of activity that resemble those observed on eukaryotic cells.

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Section: Discussionmentioning

confidence: 99%

The plasma membrane of Leishmania donovani promastigotes is the main target for CA(1–8)M(1–18), a synthetic cecropin A–melittin hybrid peptide

Díaz‐Achirica

Ubach

Guinea

et al. 1998

Biochemical Journal

102

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“…Our studies have focused on a linear, synthetic hybrid AMP composed of the first seven residues of cecropin A and residues 2-9 of the bee venom peptide mellitin. This 15residue peptide, designated CM15, retains the two-domain structure of native cecropins (28,29), with a highly cationic N-terminal region and a mostly hydrophobic C-terminal region. CM15 displays potent, broad-spectrum antimicrobial activity yet lacks the strong hemolytic activity of mellitin (30).…”

Section: Introductionmentioning

confidence: 99%

Membrane Insertion and Bilayer Perturbation by Antimicrobial Peptide CM15

Pistolesi

Pogni

Feix

2007

Biophysical Journal

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Antimicrobial peptides (AMPs) are an important component of innate immunity and have generated considerable interest as a potential new class of antibiotic. The biological activity of AMPs is strongly influenced by peptide-membrane interactions; however, for many of these peptides the molecular details of how they disrupt and/or translocate across target membranes are not known. CM15 is a linear, synthetic hybrid AMP composed of the first seven residues of the cecropin A and residues 2-9 of the bee venom peptide mellitin. Previous studies have shown that upon membrane binding CM15 folds into an alpha-helix with its helical axis aligned parallel to the bilayer surface and have implicated the formation of 2.2-3.8 nm pores in its bactericidal activity. Here we report site-directed spin labeling electron paramagnetic resonance studies examining the behavior of CM15 analogs labeled with a methanethiosulfonate spin label (MTSL) and a brominated MTSL as a function of increasing peptide concentration and utilize phospholipid-analog spin labels to assess the effects of CM15 binding and accumulation on the physical properties of membrane lipids. We find that as the concentration of membrane-bound CM15 is increased the N-terminal domain of the peptide becomes more deeply immersed in the lipid bilayer. Only minimal changes are observed in the rotational dynamics of membrane lipids, and changes in lipid dynamics are confined primarily to near the membrane surface. However, the accumulation of membrane-bound CM15 dramatically increases accessibility of lipid-analog spin labels to the polar relaxation agent, nickel (II) ethylenediaminediacetate, suggesting an increased permeability of the membrane to polar solutes. These results are discussed in relation to the molecular mechanism of membrane disruption by CM15.

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“…Included among these are the cecropins, a family of peptides typically 33-39 amino acids in length first isolated from the silk moth, Hyalophora cecropia (Hultmark et al, 1980;Steiner et al, 1981). Cecropins display broad-spectrum antimicrobial activity (Steiner et al, 1981;Andreu et al, 1985;Fink et al, 1989b) and have a general structural motif consisting of a basic N-terminal amphipathic helical domain connected to a relatively hydrophobic C-terminal domain by a flexible hinge (Holak et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Membrane Binding, Structure, and Localization of Cecropin-Mellitin Hybrid Peptides: A Site-Directed Spin-Labeling Study

Bhargava

Feix

2004

Biophysical Journal

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The interaction of antimicrobial peptides with membranes is a key factor in determining their biological activity. In this study we have synthesized a series of minimized cecropin-mellitin hybrid peptides each containing a single cysteine residue, modified the cysteine with the sulfhydryl-specific methanethiosulfonate spin-label, and used electron paramagnetic resonance spectroscopy to measure membrane-binding affinities and determine the orientation and localization of peptides bound to membranes that mimic the bacterial cytoplasmic membrane. All of the peptides were unstructured in aqueous solution but underwent a significant conformational change upon membrane binding that diminished the rotational mobility of the attached spin-label. Apparent partition coefficients were similar for five of the six constructs examined, indicating that location of the spin-label had little effect on peptide binding as long as the attachment site was in the relatively hydrophobic C-terminal domain. Depth measurements based on accessibility of the spin-labeled sites to oxygen and nickel ethylenediaminediacetate indicated that at high lipid/peptide ratios these peptides form a single alpha-helix, with the helical axis aligned parallel to the bilayer surface and immersed approximately 5 A below the membrane-aqueous interface. Such a localization would provide exposure of charged/polar residues on the hydrophilic face of the amphipathic helix to the aqueous phase, and allow the nonpolar residues along the opposite face of the helix to remain immersed in the hydrophobic phase of the bilayer. These results are discussed with respect to the mechanism of membrane disruption by antimicrobial peptides.

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The Chemical Synthesis of Cecropin D and an Analog with Enhanced Antibacterial Activity

Cited by 63 publications

References 31 publications

The plasma membrane of Leishmania donovani promastigotes is the main target for CA(1–8)M(1–18), a synthetic cecropin A–melittin hybrid peptide

The plasma membrane of Leishmania donovani promastigotes is the main target for CA(1–8)M(1–18), a synthetic cecropin A–melittin hybrid peptide

Membrane Insertion and Bilayer Perturbation by Antimicrobial Peptide CM15

Membrane Binding, Structure, and Localization of Cecropin-Mellitin Hybrid Peptides: A Site-Directed Spin-Labeling Study

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