Tolerance of Acyclic Residues in the β-Peptide 12-Helix: Access to Diverse Side-Chain Arrays for Biological Applications

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Abstract
Oligomeric backbones with well-defined conformational propensities can serve as scaffolds for displaying sets of functional groups in specific three-dimensional arrangements. β-Peptides are particularly interesting in this regard because several distinct secondary structures can be induced by appropriate choice of β-amino acid substitution pattern.3 The β-peptide 12-helix (defined by 12-membered ring CO(i)- -H−N(i + 3) hydrogen bonds) is of particular interest because this helix resembles the α-helix. To date 12-helices have been observed in β-peptides comprised exclusively of residues containing a five-membered ring constraint. Here we show that 12-helical propensity is maintained when some cyclic β-amino acid residues are replaced with more flexible acyclic residues. This result is important because use of acyclic residues greatly facilitates introduction of diverse side chains at specific sites along the 12-helix. We demonstrate the utility of this advance in the context of antibiotic design.