Structure−Activity Studies of 14-Helical Antimicrobial β-Peptides:  Probing the Relationship between Conformational Stability and Antimicrobial Potency

• Published in: Journal of the American Chemical Society 2002-10, Vol.124 (43), p.12774-12785
• Main Authors: Raguse, Tami L, Porter, Emilie A, Weisblum, Bernard, Gellman, Samuel H
• Format: Article
• Language: English
• Subjects: Analysis of complex biological substances; Analytical, structural and metabolic biochemistry; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacillus subtilis - drug effects; Biological and medical sciences; Circular Dichroism; Drug Design; Drug Stability; Enterococcus faecalis - drug effects; Escherichia coli - drug effects; Fundamental and applied biological sciences. Psychology; Microbial Sensitivity Tests; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Plants and fungi; Protein Structure, Secondary; Staphylococcus aureus - drug effects; Structure-Activity Relationship
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0270423

Antimicrobial α-helical α-peptides are part of the host-defense mechanism of multicellular organisms and could find therapeutic use against bacteria that are resistant to conventional antibiotics. Recent work from Hamuro et al. has shown that oligomers of β-amino acids (“β-peptides”) that can adopt an amphiphilic helix defined by 14-membered ring hydrogen bonds (“14-helix”) are active against Escherichia coli [Hamuro, Y.; Schneider, J. P.; DeGrado, W. F. J. Am. Chem. Soc. 1999, 121, 12200−12201]. We have created two series of cationic 9- and 10-residue amphiphilic β-peptides to probe the effect of 14-helix stability on antimicrobial and hemolytic activity. 14-Helix stability within these series is modulated by varying the proportions of rigid trans-2-aminocyclohexanecarboxylic acid (ACHC) residues and flexible acyclic residues. We have previously shown that a high proportion of ACHC residues in short β-peptides encourages 14-helical structure in aqueous solution [Appella, D. H.; Barchi, J. J.; Durell, S. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 2309−2310]. Circular dichroism of the β-peptides described here reveals a broad range of 14-helix population in aqueous buffer, but this variation in helical propensity does not lead to significant changes in antibiotic activity against a set of four bacteria. Several of the 9-mers display antibiotic activity comparable to that of a synthetic magainin derivative. Among these 9-mers, hemolytic activity increases slightly with increasing 14-helical propensity, but all of the 9-mers are less hemolytic than the magainin derivative. Previous studies with conventional peptides (α-amino acid residues) have provided conflicting evidence on the relationship between helical propensity and antimicrobial activity. This uncertainty has arisen because α-helix stability can be varied to only a limited extent among linear α-peptides without modifying parameters important for antimicrobial activity (e.g., net charge or hydrophobicity); a much greater range of helical stability is accessible with β-peptides. For example, it is very rare for a linear α-peptide to display significant α-helix formation in aqueous solution and manifest antibacterial activity, while the linear β-peptides described here range from fully unfolded to very highly folded in aqueous solution. This study shows that β-peptides can be unique tools for analyzing relationships between conformational stability and biological activity.