Cationic peptides magainins

Bacteriostatic cationic peptides Magainins, defensins, sapecins, bectenecins... 

Another kind of contact-active antimicrobial surface was achieved by tethering antimicrobial peptides to surfaces [62], If such peptides were exclusively membrane-active they could not work like in solution but would be immobilized via a polymeric spacer that could potentially cross the cell wall. The latter was demonstrated by the group of Dathe, who immobilized cationic antimicrobial peptides on PentaGels [63], Also, the well-known antimicrobial peptide magainin I... 

The cationic peptides possess two predominant themes either a hydrophobic core (often helical) with an adjacent cluster of Lys and Arg residues (e.g., melittin and cecropins) or an amphipathic helix with basic side chains aligned along one helical face (e.g., magainins and the S4 segment of the sodium channel). The basic residues promote association with the acidic... 

Micrulogix, inc., and Magainin Biotech, Inc., are two of the companies developing iratuial and recombinant cationic peptides for use as enhancers in combirtation theiapy see Chapter 16. 

Other properties may exist for cationic peptides within the host. For example, sapaecin, the insect defensin, has been found to stimulate cell proliferation of Sorcophoga embryo cells. This perhaps indicates a dual role of antimicrobial agent and developmen-tal hormone for this peptide in the flesh fly (83). Indeed, Magainin Pharmaceuticals, Inc.. Plymouth Meeting, PA has claimed to have available cationic peptides that promote reepithelialiration of damaged corneas. 

The magaiitins are a class of hnear, cationic, faciaUy amphipathic and hehcal antibacterial peptides derived from frog skin [51]. The magaiitins exhibit highly selective and potent antimicrobial activity against a broad spectrum of organisms [52, 53]. As these peptides are faciaUy amphipathic, the magainins have a cationic heli-... 

As such, the magainins provide a useful initial target for peptoid-based peptido-mimetic efforts. Since the helical structure and sequence patterning of these peptides seem primarily responsible for their antibacterial activity and specificity, it is conceivable that an appropriately designed, non-peptide helix should be capable of these same activities. As previously described (Section 1.6.2), peptoids have been shown to form remarkably stable hehces, with physical characterishcs similar to those of peptide polyprohne type-I hehces (e.g. cis-amide bonds, three residues per helical turn, and 6A pitch). A faciaUy amphipathic peptoid helix design, based on the magainin structural motif, would therefore incorporate cationic residues, hydrophobic aromatic residues, and hydrophobic aliphathic residues with threefold sequence periodicity. 

Defensins are variably cationic, relatively arginine-rich, nonglycosylated peptides comprised of 29-34 amino acid residues. Human (HNP-1) and rabbit (NP-5) defensins have been studied by NMR techniques and showed that they are rich in beta sheet structure. Although both types of defensins permeabilize the outer membrane of E. coli [31], they differ from other peptides with similar action but rich in alpha helices such as magainin, mellitin and cecropin. 

Figure 3.4 Chemical structures of mPE and molecular models of AMP. For magainin (1), residues with hydrophilic (dark grey) and hydrophobic (light grey) side chains are on opposite sides of the helix, giving rise to an amphiphilic structure for PG-1 (2), the cationic amino acids (dark grey) flank both ends of the peptide. Reproduced with permission from Y. Ishitsuka, L. Arnt, J. Majewski, S. Frey, M. Ratajczek, K. Kjaer, G.N. Tew and K.Y.C. Lee, Journal of American Chemical Society, 2006,128,13123. 2006, American Chemical Society [43]...

Magainin-2 and its analogs were found in 1993 to display sdective cytotoxidty toward carcinoma cdls in vitro and were proven to be as effective as doxorubidn in vivo via intrapetito-neal deUvety in ovarian cancer mouse modds. Several other anticancer peptides were also later found to exhibit selective cytotoxidty toward cancer cell lines in vitro, with RBCs, primary cells, or 3T3 fibroblasts generally tested as normal controls. However, even now, the selectivity of these cationic, amphipathic peptides toward cancer cells is still not well understood. 

Antimicrobial peptides have been investigated by solid-state NMR spectroscopy when they are reconstituted into oriented phospholipid bilayers. Solid-state NMR spectroscopy have shown that magainins exhibit potent antimicrobial activities when their cationic amphipathic helix is oriented parallel to the bilayer surface, a configuration found in later years for many other linear cationic amphipathic peptides. This was different for other classes of peptides. In addition the effect on the membrane was also examined by P and NMR. 

Fig. 4 (a) Antimicrobial and hemolytic activity of three a,(3-peptides (1-3), compared to AMP magainin. (b) Axial view of predicted conformations of helical SMAMPs. Cationic residues are in red, hydrophobic residues are in black. SMAMP 1 is facially amphiphilic as an 11-helix (left column), SMAMP 2 is facially amphiphilic as a 14-helix (right column), and SMAMP 3 is facially amphiphilic in neither [65]... 

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