Structure−Activity Studies of 14-Helical Antimicrobial β-Peptides: Probing the Relationship between Conformational Stability and Antimicrobial Potency
- 1 October 2002
- journal article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 124 (43), 12774-12785
- https://doi.org/10.1021/ja0270423
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.This publication has 39 references indexed in Scilit:
- Tolerance of Acyclic Residues in the β-Peptide 12-Helix: Access to Diverse Side-Chain Arrays for Biological ApplicationsJournal of the American Chemical Society, 2002
- (R,R,R)-2,5-Diaminocylohexanecarboxylic Acid, a Building Block for Water-Soluble, Helix-Forming β-PeptidesThe Journal of Organic Chemistry, 2000
- The role of position a in determining the stability and oligomerization state of α‐helical coiled coils: 20 amino acid stability coefficients in the hydrophobic core of proteinsProtein Science, 1999
- (S)-β3-Homolysine- and (S)-β3-Homoserine-Containingβ-Peptides: CD Spectra in Aqueous SolutionHelvetica Chimica Acta, 1998
- Theoretical and Experimental Circular Dichroic Spectra of the Novel Helical Foldamer Poly[(1R,2R)-trans-2-aminocyclopentanecarboxylic acid]Journal of the American Chemical Society, 1998
- Mode of action of linear amphipathic α-helical antimicrobial peptidesPeptide Science, 1998
- Membrane Pores Induced by MagaininBiochemistry, 1996
- Peptide Antibiotics and Their Role in Innate ImmunityAnnual Review of Immunology, 1995
- Improved M13 phage cloning vectors and host strains: nucleotide sequences of the M13mpl8 and pUC19 vectorsGene, 1985
- Bee and Wasp VenomsScience, 1972