Sophistication of foldamer form and function in vitro and in vivo

Abstract

Advances in the foldamer field in recent years are as diverse as the backbones of which they are composed. Applications have ranged from cellular penetration and membrane disruption to discrete molecular recognition, while efforts to control the complex geometric shape of foldamers has entered the realm of tertiary and quaternary structure. This review will provide recent examples of progress in the foldamer field, highlighting the significance of this class of compounds and the advances that have been made towards exploiting their full potential.

Figure 1

Cell-permeable foldamers bearing hydrophobic (purple) and/or cationic (blue) side chains. (a) Amphipathic hydroxyproline oligomers [13,14]; (b) Cationic β-peptide 14-helices [15,16]; (c) Aromatic amide polymer [19•]; (d) Biaryl 4G-SMoC [20••].

Figure 2

Foldamers that function as protein interaction inhibitors. Key side chains and segments in each molecule are highlighted in blue and green, respectively. (a) (α/β+α)-peptide that binds Bcl-x_L with IC₅₀ = 29 nM [28••]. (b) Peptoid that binds hDM2 with IC₅₀ = 6.6 μM [30•]. (c) Peptoid that inhibits the proteasome 19S regulatory particle with IC₅₀ ~ 3 μM in a protein unfolding assay [23••]. (d) Synthetic transcription factor mimic with K_d = 11.6 μM for GST-KIX fusion protein [24••]. (e) Biaryl scaffold that binds the estrogen receptor with IC₅₀ = 4.2 μM [31••]. (f) Arylamide derivative that binds calmodulin with K_i = 7.10 nM [32•].

Figure 3

Higher-order foldamer structures. (a) The threaded-loop structure of the peptoid nonamer, Nspe₉, is facilitated by hydrogen-bonds (green dashed lines) [49•]. (b) The octameric helical-bundle structure of the β³-peptide, Zwit-1F, which resembles two hands with four fingers cupped over each other. (c) A side view of the Zwit-1F helical bundle depicting the packing of the hydrophobic core of β³-hLeu residues (green sticks). (d) One tetramer of the helical bundle, Zwit-1F, illustrating the packing between backbone methylenes (spheres) of neighboring helices [56••]. (e) A side view of the α/β-peptide tetramer inspired by the α-peptide tetramer, GCN4-pLI. The α-amino acid residues are displayed in blue, while the β-amino acid residues are shown in green. (f) A top-down view of the α/β-peptide tetramer depicted in (e) [57•].