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Review
. 2015 Aug 31;4(3):540-55.
doi: 10.3390/biology4030540.

Multi-Facial, Non-Peptidic α-Helix Mimetics

Maryanna E Lanning  1 , Steven Fletcher  2   3
Affiliations
Review

Multi-Facial, Non-Peptidic α-Helix Mimetics

Maryanna E Lanning et al. Biology (Basel). .

Abstract

α-Helices often recognize their target proteins at protein-protein interfaces through more than one recognition face. This review describes the state-of-the-art in the design of non-peptidic α-helix mimetics that reproduce functionality from multiple faces of an α-helix.

Keywords: Bak; Bcl-2; Bim; HMD2; amphipathic; cancer; p53; protein–protein interaction; proteomimetic; α-helix mimetic.

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Figures

Figure 1
Figure 1
An α-helix (left) and a terphenyl-based α-helix mimetic (right), highlighting the amino acid side chains located on one face. Colours correspond to amino acid side chains and their respective surrogates.
Figure 2
Figure 2
Single-faced, synthetic α-helix mimetics. Dashed lines represent hydrogen bonds.
Figure 3
Figure 3
Multi-sided, single-faced, synthetic α-helix mimetics. Rx and Ry may be solubilizing groups or moieties to improve cell uptake, for example.
Figure 4
Figure 4
Oligoarylamides as single-faced helix mimetics.
Figure 5
Figure 5
Two-faced bis-benzamide helix mimetics. Dashed lines represent hydrogen bonds.
Figure 6
Figure 6
A two-faced helix mimetic centered on a benzoylurea scaffold. Dashed lines represent a bifurcated hydrogen bond.
Figure 7
Figure 7
An intramolecular hydrogen bond (dashed line) influences the projection of side-chains from opposing faces of a diphenylacetylene scaffold.
Figure 8
Figure 8
Appropriately functionalized anthraquinones (left) and acridines (right) have disrupted the Bim–Mcl-1 PPI through two-faced mimicry of the Bim-BH3 α-helix.
Figure 9
Figure 9
2,6,9-Tri-substitution of a purine scaffold permits the mimicry of two faces of an α-helix, according to the disruption of the Mcl-1–Bak-BH3 PPI.
Figure 10
Figure 10
In addition to their ability to mimic the epitopes of β-turns and one face of an α-helix, benzodiazepines have been introduced as scaffolds to reproduce functionality displayed from two faces of an α-helix.
Figure 11
Figure 11
A phenyl-piperazine-triazine helix mimetic disrupts the Bim–Mcl-1 PPI. Synthetic strategies to vary the ethyl group should allow the additional mimicry of the i + 5 position on the opposing face.
Figure 12
Figure 12
A novel helix mimetic that projects functionality in a similar orientation to five of seven residues spanning two turns of an α-helix.
See this image and copyright information in PMC

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