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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.

A versatile synthesis of pyridazine-based small molecule α-helix mimetics (A) is presented. Modular C-C, C-N, and C-O bond-forming reactions allow for the inclusion of a variety of aliphatic, basic, aromatic, and heteroaromatic side chain moieties. This robust synthesis is suitable for the preparation of small pyridazine-based libraries. [ABSTRACT FROM AUTHOR]

A previously reported terephthalamide-based α-helix mimetic was modified by introducing a pyridine nitrogen and converting a tertiary amide to a secondary amide, which afforded a second intramolecular hydrogen bond to further influence the projection of the i , i + 3/4, and i + 7 side chains from the same face of the scaffold. The existence of two intramolecular hydrogen bonds was confirmed by 1 H NMR titration studies and molecular dynamics simulations. By virtue of the short and efficient route described herein, access to this new family of α-helix mimetics is straightforward. Moreover, the inclusion of a chiral center will permit the interrogation of the stereochemical impact on ligand–receptor binding. [ABSTRACT FROM AUTHOR]

The development of protein–protein interaction (PPIs) inhibitors represents a challenging goal in chemical biology and drug discovery. PPIs are problematic targets because they involve large surfaces with less well defined features and recognition motifs that are less amenable to conventional experimental and computational ligand discovery methodologies. α-Helix mediated PPIs represent a sub group with a clearly defined interface and thus may be more amenable to the development of generic ligand discovery methods. Indeed, this is borne out in numerous studies using peptides covalently constrained into a helical conformation resulting in improvement of myriad biophysical and cellular properties. It is however desirable to have small molecule alternatives: a helix mimetic ( proteomimetic ) is a generic small molecule scaffold that projects functional groups in a similar spatial orientation so as to mimic the presentation of key amino acid side chains from the helix that mediates the PPI. The first true example of a helix mimetic was described over a decade ago however this approach has not yet been elaborated to the extent that it receives similar levels of attention to constrained peptides. This review explores recent significant developments in the area of small molecule α-helix mimetics and provides a critical overview of success stories, potential limitations of the approach, and areas for future development. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: A range of small molecule scaffolds have been shown to act as structural and functional mimics of α-helices by mimicking the i, i+4, and i+7 positions, often found at the interface of PPIs. These molecules, though potent, possess complicating features—either low water solubility, or maintenance of conformation by hydrogen-bonding networks. We have addressed these limitations by developing a scaffold with increased water solubility. Herein we present a rapid synthetic pathway to a library of 56 compounds based on a 5-6-5 scaffold, containing an imidazole-phenyl-thiazole core; the route is flexible and allows rapid installation of different substituents via high-yielding Ullman and Suzuki couplings and Hantsch thiazole syntheses. [Copyright &y& Elsevier]

Protein-protein interactions (PPIs) play a central role in all biological processes and have been the focus of intense investigations from structural molecular biology to cell biology for the majority of the last two decades and, more recently, are emerging as important targets for pharmaceuticals. A common motif found at the interface of PPIs is the α-helix, and apart from the peptidic structures, numerous nonpeptidic small molecules have been developed to mimic α-helices. The first-generation terphenyl scaffold is able to successfully mimic key helix residues and disrupt relevant interactions, including Bcl-xL-Bak interactions that are implicated in apoptosis mechanism. These scaffolds were designed and evaluated in silico. Analysis revealed that substituents on aromatic scaffolds can efficiently mimic side-chain surfaces. Unfortunately, the literature describes a long and difficult procedure to access these aromatic-based scaffolds. The search for new simpler methodology is the aim of the research of our medicinal chemistry team. On the basis of structural requirements, we developed a program concerning the synthesis of new oligo(het)aryl scaffolds produced by iterative couplings of boronic species (garlanding) in which substituents on rings project functionality in spatial orientations that mimic residues of an α-helix. [ABSTRACT FROM AUTHOR]

Abstract: The design and synthesis of α-helix peptidomimetics using inverse electron demand Diels–Alder reactions is described. The potency of the resulting pyridazine-based library to disrupt the Bak/Bcl-XL interaction was tested using an in vitro fluorescence polarization assay. [Copyright &y& Elsevier]

Abstract: An intramolecularly hydrogen bonded enaminone scaffold was designed and synthesized in order to mimic the i, i +4, and i +7 residues of an α-helix. The resonance stabilized vinylogous amide group serves as an aromatic ring isostere and allows the positioning and angular projection of the R-groups in a manner similar to an α-helix. [Copyright &y& Elsevier]

Abstract: Inspired by the topological similarity between ladder-like cyclic ether skeletons and α-helical peptides, a trans-fused 6/6/6/6 tetracyclic ether containing two hydroxyl groups separated by a distance of 4.8Å was designed as a scaffold for a nonpeptidic α-helix mimetic. Two alkyl guanidinium groups were attached to the hydroxyl groups to develop a synthetic receptor for the specific recognition of i +4 spaced aspartate pairs on the surface of an α-helical peptide. A circular dichroism (CD) titration showed that this mode of molecular recognition stabilizes α-helical structures of peptides containing i +4 spaced aspartate pairs. [Copyright &y& Elsevier]