Antitumour activity and specificity as a function of substitutions in the lipophilic sector of helical lactoferrin-derived peptide

A peptide L5 (PAWIRKAFRWAWRMLKKAA), derived from the N-terminal alpha-helical region of bovine lactoferrin (LFB 14-31), that is highly active against several tumour cell lines was reported earlier. In this study, a number of L5 analogues were designed in order to investigate how subsequent replacements of the aromatic amino acids in L5 with three amino acids representing different structural parameters influenced antitumour activity and tumour cell specificity relative to normal human cells. The Trp residues were substituted by Lys, Ile or Ala, while the Phe residue was substituted with Ala. The resulting peptides were investigated for their activity against prokaryotic cells, four tumour cell lines, human lung fibroblasts and human erythrocytes. Most of the peptides were highly active against both E. coli and S. aureus. The peptides were more active against the tumour cell lines than against normal eukaryotic cells but the activity against normal fibroblasts varied more among the peptides than did their antitumour activities. The results revealed that aromatic residues located opposite the cationic sector in L5 were more critical for antitumour activity than were aromatic residues located adjacent to the cationic sector. The biological responses for the peptides against tumour cell lines, fibroblasts, S. aureus (but not E. coli), were highly correlated with the amino acid descriptors used in our QSAR model. The result obtained from the QSAR study identified specific structural features that were important for lytic activity and membrane specificity. Certain structural proper-ties in positions 3, 9 and 11 were shown to be important for antitumour activity, while additional structural properties in position 7 were found to be important with respect to tumour cell specificity. This information may offer a possibility for de novo design of an antitumour peptide with an improved therapeutic index. Copyright (C) 2003 European Peptide Society and John Wiley Sons, Ltd.