Design, Synthesis, and Evaluation of an α-Helix Mimetic Library Targeting Protein−Protein Interactions

Abstract

-The design and solution-phase synthesis of an α-helix mimetic library as an integral component of a small molecule library targeting protein-protein interactions are described. The iterative design, synthesis, and evaluation of the candidate α-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 × 20 × 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i+4, i+7 amino acid side chains of an α-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead α-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an α-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.

Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer

“…Since our initial report in 2007 (ref. 26), the ability of the oligo-benzamide scaffolds to mimic helical structures and disrupt PPIs have been further established [33][34][35][36] . We also demonstrated that the oligo-benzamidebased peptidomimetics can easily be synthesized by using simple and uncomplicated reactions with high yields 30 .…”

Synthesis and screening of small-molecule α-helix mimetic libraries targeting protein–protein interactions

“…One such scaffold is aromatic oligoamides 2, which have structural rigidity due to intramolecular hydrogen bonding (Figure 1c). Because they are easily prepared by a modular synthesis and have improved water solubility [32,33], aromatic oligoamides are an attractive scaffold and widely utilized as a-helix mimetics [32,[34][35][36][37][38][39][40][41]. For example, recently, Wilson and co-workers have utilized trisbenzamides as an a-helix mimetic scaffold to develop inhibitors of the interaction between hypoxia inducible factor-1a (HIF-1a) and p300 [39 ].…”

“…One such example is a positional-scanning type of strategy developed by Boger and co-workers to efficiently screen a large number of a-helix mimetic small molecules [35,65]. They designed an oligoamide scaffold 24 as a-helix mimetics and developed a solution-phase synthetic route via modified peptide coupling conditions ( Figure 4a).…”

Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein

“…Indeed, there are only a few reports on the use of HTS to identify α-helix mimetic small molecules (39)(40)(41). The most frequently used method to identify α-helix mimetics is a competitive binding assay, using a fluorescence polarization (FP).…”