-
[show abstract]
[hide abstract]
ABSTRACT: This review discusses antibacterial peptides from the perspective of development into clinically useful chemotherapeutic drugs using short lactoferricin based peptides as examples. The review shows how important features for antibacterial activity can be identified and explored using the molecular properties of a range of natural and non-natural amino acids. The results have been further refined quantitatively using a "soft-modelling" approach where important structural parameters that influence the antibacterial activity of 15-residue model peptides were identified. The review describes how this knowledge is utilised to generate pharmacophores for antibacterial efficacy. These pharmacophores turn out to be surprisingly small and relatively consistent between typical Gram-negative and Gram-positive bacteria leading to the discovery of a novel class of short synthetic cationic antimicrobial peptides. These compounds are found to have high antibacterial activity against several bacterial strains that are resistant to commercial antibiotics, and are promising as future clinical candidates for treatment of infections caused by several clinically relevant pathogens.
Current Medicinal Chemistry 02/2007; 14(1):1-18. · 4.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Pentadecapeptides based on modified murine lactoferricin (LFM) sequences show varying degrees of antibacterial activity against Escherichia coli and Staphylococcus aureus. By means of projections to latent structures (PLS), a good correlation is obtained if the biological activity is modelled as a function of variables describing peptide properties, e.g. alpha-helicity, hydrophobicity/hydrophilicity and charge. Using variables derived from a principal component analysis (PCA) of all naturally occurring amino acids, it is possible to describe the amino acid content of the peptides using three variables per amino acid position. The resulting descriptor matrix is then used to develop quantitative structure-activity relationships (QSAR). It is shown that the theoretically derived descriptors model the activity of the peptides better than the earlier model, and that properties of the peptides other than antibacterial activity can be predicted.
Journal of Peptide Science 03/2001; 7(2):74-81. · 1.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: LFM W8 is a synthetic 15-residue lactoferricin derivative (H2N-EKCLRWQWEMRKVGG-COOH), corresponding to residues 16-30 of the mature murine lactoferrin protein except that the asparagine residue in position 8 of the native peptide is replaced with tryptophan. We have previously reported that the two tryptophan residues in positions 6 and 8 are of crucial importance for the antibacterial activity of many lactoferricin derivatives but, despite fulfilling this requirement, LFM W8 is inactive against Escherichia coli and Staphylococcus aureus. In order to solve this puzzle, a quantitative structure-antibacterial activity relationship study of synthetic LFM W8 derivatives was performed by replacing the glutamate residues in positions 1 and 9 with arginine or alanine, and the valine residue in position 13 with tyrosine. The results from the study were analyzed using multivariate data analysis. The derived mathematical model clustered the peptides into distinct groups which reflected their antibacterial activities, pointed out correlations between different structural parameters, highlighted the structural parameters that were important for antibacterial activity, and enabled us to predict the activity of a 15-residue bovine lactoferricin derivative. The results showed that net charge and micelle affinity, as determined from the ratio of alpha-helicity in sodium dodecyl sulfate micelles and in 1,1,1,3,3,3-hexafluoro-2-propanol, were the most important structural parameters affecting antibacterial activity. The most active derivative, LFM R1,9 W8 Y13, displayed a minimal inhibitory concentration of 10 and 12 microM against E. coli and S. aureus, respectively. This represented more than 50-fold and 40-fold increases in antibacterial activity, respectively, compared with LFM W8.
European Journal of Allergy and Clinical Immunology 03/2001; 57(2):127-39. · 1.30 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: :LFM W8 is a synthetic 15-residue lactoferricin derivative (H2N-EKCLRWQWEMRKVGG-COOH), corresponding to residues 16-30 of the mature murine lactoferrin protein except that the asparagine residue in position 8 of the native peptide is replaced with tryptophan. We have previously reported that the two tryptophan residues in positions 6 and 8 are of crucial importance for the antibacterial activity of many lactoferricin derivatives but, despite fulfilling this requirement, LFM W8 is inactive against Escherichia coli and Staphylococcus aureus. In order to solve this puzzle, a quantitative structure-antibacterial activity relationship study of synthetic LFM W8 derivatives was performed by replacing the glutamate residues in positions 1 and 9 with arginine or alanine, and the valine residue in position 13 with tyrosine. The results from the study were analyzed using multivariate data analysis. The derived mathematical model clustered the peptides into distinct groups which reflected their antibacterial activities, pointed out correlations between different structural parameters, highlighted the structural parameters that were important for antibacterial activity, and enabled us to predict the activity of a 15-residue bovine lactoferricin derivative. The results showed that net charge and micelle affinity, as determined from the ratio of α-helicity in sodium dodecyl sulfate micelles and in 1,1,1,3,3,3-hexafluoro-2-propanol, were the most important structural parameters affecting antibacterial activity. The most active derivative, LFM R1,9 W8 Y13, displayed a minimal inhibitory concentration of 10 and 12 µm against E. coli and S. aureus, respectively. This represented more than 50-fold and 40-fold increases in antibacterial activity, respectively, compared with LFM W8.
European Journal of Allergy and Clinical Immunology 01/2001; 57(2):127-139. · 1.30 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Lactoferricins are a class of antibacterial peptides isolated after gastric-pepsin digest of the mammalian iron-chelating-protein lactoferrin. For investigation of antibacterial activity, we prepared short synthetic derivatives of bovine, human, caprine, murine and porcine lactoferricins with 15-amino-acid residues of high sequence homology. The peptides corresponded to amino-acid residues 17-31 of the mature bovine lactoferrin. Only the bovine and caprine derivatives displayed measurable antibacterial activity, with the bovine one having a minimal inhibitory concentration of 24 microM and being 10 times more active than the caprine one against Escherichia coli. An alanine-scan of the bovine lactoferricin derivative was performed to identify specific amino acids that were important for the antibacterial activity. We found that neither of the two tryptophan residues (Trp 6 and Trp 8) present in the bovine lactoferricin derivative could be replaced by alanine without a major loss of antibacterial activity. The other lactoferricin derivatives tested contained only one tryptophan residue (Trp 6). Modified human, caprine and porcine lactoferricin derivatives containing two tryptophan residues (Trp 6 and Trp 8) displayed minimal inhibitory concentrations of 74, 174 and 219 microM, respectively, which represented up to a six-fold increase in antibacterial activity. The alanine-scan also revealed that the antibacterial activity was increased when acetamidomethyl-protected cysteine and unprotected glutamine (Cys 3 and Gln 7) were replaced with alanine. Only the bovine lactoferricin derivative and a few of its alanine-modified derivatives displayed measurable activity against Staphylococcus aureus.
European Journal of Allergy and Clinical Immunology 12/2000; 56(5):265-74. · 1.30 Impact Factor
