Peptoid Mimics of Antibacterial Peptides

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. 

Nssh= (S)-N-(sec-butyl)glycine Nspe= (S)-N-(l-phenylethyl)glycine Ngch = (S)-N-(l-cyclohexyl-ethyl)glycine NLys = N-(4-aminobutyl)glycine. 

Certain of these peptoid antibiotics are also selective for bacterial, rather than mammalian, cells. The selectivity of these peptoids has been measured in terms of their capacity to cause hemolysis of human erythrocytes at or near their MIC (Tab. 1.3). Interestingly, the amount of hemolysis induced by these peptoids correlates well with their hydrophobicity as there is an increasing extent of hemolysis as molecular hydrophobicity increases. These results suggest that highly hydro-phobic compounds of this class are poorly selective antibiotics. The most active antibacterial peptoids, T2-15 and T3-12, have quite low hemolytic activity near their MICs. Although highly antibacterial in vitro, T3-17 is also very hemolytic at its MIC value. 

In summary, these recently obtained results demonstrate that certain amphi-pathic peptoid sequences designed to mimic both the helical structure and approximate length of magainin helices are also capable of selective and biomimetic antibacterial activity. These antibacterial peptoids are helical in both aqueous buffer and in the presence of lipid vesicles. Ineffective (non-antibacterial) peptoids exhibit weak, random coil-like CD, with no spectral intensification in the presence of lipid vesicles. Selective peptoids exhibit stronger CD signals in bacterial-mimetic vesicles than in mammalian-mimetic vesicles. Non-selective peptoids exhibit intensely helical CD in both types of vesicles. 

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