Environment-independent 14-helix formation in short beta-peptides: striking a balance between shape control and functional diversity

We report a significant and unanticipated advance in the study of beta-amino acid-based foldamers: a small proportion of highly preorganized residues can impart high stability to a specific helical secondary structure in water. Most of the residues in these beta-peptides (2 and 3) are intrinsically flexible. Flexible beta-amino acids can be readily and enantiospecifically prepared in functionally diverse forms, but preorganized residues with side chains are rare and challenging to synthesize. Our findings demonstrate that interspersing a few copies of an unfunctionalized but rigid residue among a larger number of flexible residues with diverse side chains is a viable strategy for creating beta-peptides that adopt the 14-helix conformation and therefore display side chains in a predictable spatial arrangement. These results are significant because they enhance the prospects of developing beta-peptides with useful activities.     

Secondary structural preferences of 2,2-disubstituted pyrrolidine-4-carboxylic acid oligomers: beta-peptide foldamers that cannot form internal hydrogen bonds

We examine a new class of beta-peptides, 2,2-disubstituted pyrrolidine-4-carboxylic acid oligomers, and show that they manifest discrete conformational preferences despite the impossibility of internal hydrogen bonding. Numerous beta-peptide families have been described that display specific secondary structural preferences, but all of the conformations characterized in detail so far have contained internal hydrogen bonds. Internal hydrogen bonding is observed within the most common secondary structures of conventional peptides as well. Identifying foldamers in which shape control is independent of hydrogen bonding is significant in two ways. At a fundamental level, foldamers in this small but growing class are interesting because their shapes are controlled by distinctive networks of noncovalent forces. At a practical level, non-hydrogen bonded foldamers may be useful in biomedical applications because the low intrinsic polarity of their backbones may promote bioavailability.     

Non-hydrogen-bonded secondary structure in beta-peptides: evidence from circular dichroism of (S)-pyrrolidine-3-carboxylic acid oligomers and (S)-nipecotic acid oligomers

[formula: see text] Homooligomers of beta-amino acids (S)-3-pyrrolidine-3-carboxylic acid (PCA) and (S)-nipecotic acid (Nip) were studied by circular dichroism (CD) in methanol. In each series, a profound change in the far-UV CD spectrum was observed from monomer to tetramer, but little change was observed from tetramer to hexamer. A comparable pattern is observed in the CD spectra of short proline oligomers. We conclude that both PCA and Nip oligomers with > or = four residues adopt a characteristic secondary structure.     

Unexpected relationships between structure and function in alpha,beta-peptides: antimicrobial foldamers with heterogeneous backbones

We describe our first effort to design antimicrobial alpha/beta-peptides based upon their helical folding behavior. alpha/beta-Peptide 3 (above), designed as a scrambled negative control, exhibited the most favorable activity profile, combining high antimicrobial activity with low hemolytic activity. This finding suggests that design principles focused primarily on structures that adopt globally amphiphilic structures may exclude productive possibilities from evaluation.     

Biocidal activity of polystyrenes that are cationic by virtue of protonation

[structure: see text] Poly(1) kills bacteria (Gram-positive and -negative) and lyses human erythrocytes; this biocidal profile is similar to that of the peptide toxin mellitin. Poly(1) has antibacterial activity comparable to that of a potent derivative of the host defense peptide magainin II, but lacks magainin's selectivity for bacteria over erythrocytes. An analogous N-quaternized polymer, poly(3), is less biocidal than poly(1), suggesting that reversible N-protonation leads to greater biocidal activity than does irreversible N-quaternization.