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

Abstract

Antimicrobial alpha-helical alpha-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 beta-amino acids ("beta-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 beta-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 beta-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 beta-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 (alpha-amino acid residues) have provided conflicting evidence on the relationship between helical propensity and antimicrobial activity. This uncertainty has arisen because alpha-helix stability can be varied to only a limited extent among linear alpha-peptides without modifying parameters important for antimicrobial activity (e.g., net charge or hydrophobicity); a much greater range of helical stability is accessible with beta-peptides. For example, it is very rare for a linear alpha-peptide to display significant alpha-helix formation in aqueous solution and manifest antibacterial activity, while the linear beta-peptides described here range from fully unfolded to very highly folded in aqueous solution. This study shows that beta-peptides can be unique tools for analyzing relationships between conformational stability and biological activity.

High-Resolution Structure of a β-Peptide Bundle

“…Parallel helical pairs associate the aromatic face of an internal helix with the salt-bridge face of a terminal helix, with β 3 -E 1 and β 3 -O 10 forming electrostatic contacts with β 3 -O 3 and β 3 -D 12 , respectively. In addition, the β 3 -F side chains exhibit a degree of hydrophobic packing from the side chain carbon atoms of opposing β 3 -D 6 and β 3 -O 9 . Despite the differences in specific interactions, both helical arrangements are tightly packed, with parallel and antiparallel interfaces burying 796 and 784 Å 2 of surface area, respectively, approximately 50% of a monomer.…”

Inhibition of Herpes Simplex Virus Type 1 Infection by Cationic β-Peptides

“…Helical ␤-peptides have been shown to mimic the antimicrobial activities of host-defense peptides (37,43,44,49). This activity required the design of sequences that lead to global segregation of cationic and hydrophobic residues on opposite sides of the helix.…”

A Theoretical Study of <i>β</i>-Amino Acid Conformational Energies and Solvent Effect

“…The stability of β-peptides, important for biological activity, makes them good candidates for useful drugs. [18] It has been shown that foldamers comprising a mixture of α-, β-, and γ-amino acid residues are not degraded by proteases which bodes well for biological application [26] [27].…”