LFM W8 is a synthetic 15-residue lactoferricin derivative (H2N-EKCLRWQWEMRK
VGG-COOH), corresponding to residues 16-30 of the mature murine lactoferrin
protein except that the asparagine residue in position 8 of the native pep
tide 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 fulfi
lling this requirement, LFM W8 is inactive against Escherichia coli and Sta
phylococcus 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 be
tween different structural parameters, highlighted the structural parameter
s 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 o
f alpha -helicity in sodium dodecyl sulfate micelles and in 1,1,1.3,3,3-hex
afluoro-2-propanol, were the most important structural parameters affecting
antibacterial activity. The most active derivative, LFM R1,9 W8 Y13, displ
ayed a minimal inhibitory concentration of 10 and 12 muM against E. coli an
d S. aureus, respectively. This represented more than 50-fold and 40-fold i
ncreases in antibacterial activity, respectively, compared with LFM W8.