Controlling Helix Formation in the γ-Peptide Superfamily: Heterogeneous Foldamers with Urea/Amide and Urea/Carbamate Backbones

摘要

Structures and functions of biopolymers have inspired the design, synthesis, and characterization of a multitude of synthetic oligomeric backbones with well-defined and predictable folding patterns, termed foldamers. The diversity of foldamer structures originates from the chemical diversity of constituent units which have been developed to impose conformational restriction and promote folding. Like nucleic acids and proteins, many foldamer backbones are built from one type of subunit, and diversity is generally created through side chains (e.g. aliphatic β and γ peptides, aromatic 5 peptides, hydrazinopeptides, aminoxy peptides, aliphatic oligoureas). Foldamer synthesis is, however, not limited to homogenous backbones. Approaches based on sequences combining two or more types of monomers, that is, heterogeneous foldamers, have recently been the subject of much interest as they considerably expand the diversity of foldamer backbones accessible from a limited set of building blocks. For example, peptide helices with different surface topologies and functions have been created by combining aliphatic α-, β-, and γ-amino acid residues at different periodicities. Alternatively, various combinations of iso-steric building units may be used to create isomorphic foldamer backbones which subtly differ from their homoge- neous counterparts in terms of physicochemical properties (e.g. water solubility, backbone polarity, conformational stability, side-chain projection) and ultimately biological activities. We have previously demonstrated that heterogeneous backbone sequences consisting of isosteric amide (A) and urea (U) units with proteinogenic side chains (Figure 1 a) can be used to tune and optimize biological activities of corresponding homooligomers (i.e., helical γ~4-peptides A_n and N,N'-linked oligoureas U?). Whereas amphi-philic helical γ~4-peptides A_n, designed to mimic host defense peptides, failed to display any significant antimicrobial activity, the insertion of discrete A units in U_n sequences led to active sequences with increased selectivity for bacterial membranes compared to the cognate U_n homooligomer.