Important structural features of 15-residue lactoferricin derivatives and methods for improvement of antimicrobial activity

Abstract

This review focuses on important structural features affecting the antimicrobial activity of 15-residue derivatives of lactoferricins. Our investigations are based on an alanine-scan of a 15-residue bovine lactoferricin derivative that revealed the absolute necessity of two tryptophan residues for antimicrobial activity. This "tryptophan-effect" was further explored in homologous derivatives of human, caprine, and porcine lactoferricins by the incorporation of one additional tryptophan residue, and by increasing the content of tryptophan in the bovine derivative to five residues. Most of the resulting peptides display a substantial increase in antimicrobial activity. To identify which molecular properties make tryptophan so effective, a series of bovine lactoferricin derivatives were prepared containing non-encoded unnatural aromatic amino acids, which represented various aspects of the physicochemical nature of tryptophan. The results clearly demonstrate that tryptophan is not unique since most of the modified peptides were of higher antimicrobial potency than the native peptide. The size and three-dimensional shape of the inserted "super-tryptophans" are the most important determinants for the high antimicrobial activity of the modified peptides. This review also describes the use of a "soft-modeling" approach in order to identify important structural parameters affecting the antimicrobial activity of modified 15-residue murine lactoferricin derivatives. This QSAR-study revealed that the net charge, charge asymmetry, and micelle affinity of the peptides were the most important structural parameters affecting their antimicrobial activity.

Length Effects in Antimicrobial Peptides of the (RW)nSeries

“…The role of RW-rich motifs in AMPs has been investigated using quantitative-structure-activity relationships (QSAR) (24,45,46,53). Truncated peptide sequences from indolicidin and lactoferricin with conserved RW motifs retain antimicrobial activity even when their original secondary structure is lost (45,53), suggesting that R and W content alone correlates with activity.…”

“…Truncated peptide sequences from indolicidin and lactoferricin with conserved RW motifs retain antimicrobial activity even when their original secondary structure is lost (45,53), suggesting that R and W content alone correlates with activity. QSAR analysis of the antimicrobial activities of R and W peptides suggests that charge and multiple W side chains are necessary, while W can be replaced by analogs with bulkier side chains (24,46,48). The results also suggest that, in short peptides, the order of amino acids is less important than the overall composition with respect to cationic and lipophilic residues (41,46,47).…”

“…QSAR analysis of the antimicrobial activities of R and W peptides suggests that charge and multiple W side chains are necessary, while W can be replaced by analogs with bulkier side chains (24,46,48). The results also suggest that, in short peptides, the order of amino acids is less important than the overall composition with respect to cationic and lipophilic residues (41,46,47).…”

“…The guanidinium group of R has a more dispersed positive charge than the single amine of K, possibly enhancing electrostatic interactions between peptides and the negatively charged bacterial membrane surface (39,53). On the other hand, the bulkier W side chain may ensure more efficient interaction with membrane surfaces, allowing peptides to partition in the bilayer interface, in contrast with other nonpolar side chains such as F, P, or Y (46,56). Recently, consideration of electrostatic effects, including dipole and quadrupole moments of R and W side chains, respectively, suggests that these properties may be involved in the ability to form hydrogen bonds once peptides associate with membranes (27,53,58).…”

Cationic Antimicrobial Peptides

“…Bal has the same size as the indole ring, but because of the lower electronegativity of the sulfur atom in the five-membered ring, its dipole moment is reduced compared to W ( Table 2). It has no considerable amphipathic structure and does not have the hydrogen bonding characteristics of W [123]. Both 1MeW and Bal residues are more hydrophobic than W. This appeared in the higher t R -values of c- * The classification is based on the chemical structures of the residues.…”