Abstract
Inhibition of protein–protein interactions (PPIs) represents a major challenge in chemical biology and drug discovery. α-Helix mediated PPIs may be amenable to modulation using generic chemotypes, termed “proteomimetics”, which can be assembled in a modular manner to reproduce the vectoral presentation of key side chains found on a helical motif from one partner within the PPI. In this work, it is demonstrated that by using a library of N-alkylated aromatic oligoamide helix mimetics, potent helix mimetics which reproduce their biophysical binding selectivity in a cellular context can be identified.
Highlights
Protein–protein interactions (PPIs) mediate all biological processes and are actively involved in the development and progression of disease.[1]
Strictly speaking our goal was not to identify inhibitors of a specific PPI, we identified potent inhibitors of p53/hDM2 and the B-cell lymphoma-2 (Bcl-2) family PPIs which induce apoptosis, and this may
The Bcl-2 family plays a central role in the regulation of apoptosis through control of mitochondrial outer membrane permeabilization.[31]
Summary
Protein–protein interactions (PPIs) mediate all biological processes and are actively involved in the development and progression of disease.[1]. A fluorescently labelled phalloidin.[44] To promote cell motility and invasion, cancer cells alter the cytoskeleton and a number of reports have indicated a relationship between this modification and the activity of p53.[44] To provide a qualitative interpretation of the data, the data are shown in Figure 2 b as a heat map (a summary of all the data from the apoptosis assay for the full library of compounds can be found in Table S2 in the Supporting Information).
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