Interplay among Folding, Sequence, and Lipophilicity in the Antibacterial and Hemolytic Activities of α/β-Peptides

• Published in: Journal of the American Chemical Society 2007-01, Vol.129 (2), p.417-428
• Main Authors: Schmitt, Margaret A, Weisblum, Bernard, Gellman, Samuel H
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacillus subtilis - drug effects; Chromatography, High Pressure Liquid; Circular Dichroism; Enterococcus faecium - drug effects; Erythrocytes - drug effects; Escherichia coli - drug effects; Hemolysis - drug effects; Humans; Hydrophobic and Hydrophilic Interactions; Magnetic Resonance Spectroscopy - methods; Microbial Sensitivity Tests; Peptide Hydrolases - chemistry; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Protein Conformation; Protein Folding; Protein Structure, Secondary; Sensitivity and Specificity; Staphylococcus aureus - drug effects; Structure-Activity Relationship
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0666553

Host-defense peptides inhibit bacterial growth but manifest relatively little toxicity toward eukaryotic cells. Many host-defense peptides adopt α-helical conformations in which cationic side chains and lipophilic side chains are segregated to distinct regions of the molecular surface (“globally amphiphilic helices”). Several efforts have been made to develop unnatural oligomers that mimic the selective antibacterial activity of host-defense peptides; these efforts have focused on the creation of molecules that are globally amphiphilic in the preferred conformation. One such endeavor, from our laboratories, focused on helix-forming α/β-peptides, i.e., oligomers containing a 1:1 pattern of α- and β-amino acid residues in the backbone [Schmitt, M. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2004, 126, 6848−6849]. We found, unexpectedly, that the most favorable biological activity profile was displayed by a “scrambled” sequence, which was designed not to be able to form a globally amphiphilic helix. Here we report new data, involving an expanded set of α/β-peptides, from experiments designed to elucidate the origins of this surprising result. In addition, we evaluate the susceptibility of α/β-peptides to proteolytic degradation. Our results support the hypothesis that the ability to adopt a globally amphiphilic helical conformation is not a prerequisite for selective antibacterial activity. This conclusion represents a significant advance in our understanding of the relationship among molecular composition, conformation, and biological activity. Our results should therefore influence the design of other unnatural oligomers intended to function as antibacterial agents.