alpha-Helix mimetics as inhibitors of protein-protein interactions.
نویسندگان
چکیده
The inhibition of protein-protein interactions using small molecules is a viable approach for the treatment of a range of pathological conditions that result from a malfunctioning of these interactions. Our strategy for the design of such agents involves the mimicry of side-chain residues on one face of the alpha-helix; these residues frequently play a key role in mediating protein-protein interactions. The first-generation terphenyl scaffold, with a 3,2',2''-substitution pattern, is able to successfully mimic key helix residues and disrupt therapeutically relevant interactions, including the Bcl-X(L)-Bak and the p53-hDM2 (human double minute 2) interactions that are implicated in cancer. The second- and third-generation scaffolds have resulted in greater synthetic accessibility and more drug-like character in these molecules.
منابع مشابه
Selective and Potent Proteomimetic Inhibitors of Intracellular Protein–Protein Interactions†
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...
متن کاملOrthogonal functionalisation of α-helix mimetics† †Electronic supplementary information (ESI) available: Additional binding data and fluorescence characterisation. Experimental procedures and characterisation of all new compounds. See DOI: 10.1039/c4ob00915k Click here for additional data file.
α-Helix mediated protein-protein interactions are of major therapeutic importance. As such, the design of inhibitors of this class of interaction is of significant interest. We present methodology to modify N-alkylated aromatic oligoamide α-helix mimetics using 'click' chemistry. The effect is shown to modulate the binding properties of a series of selective p53/hDM2 inhibitors.
متن کاملRational Design of Topographical Helix Mimics as Potent Inhibitors of Protein–Protein Interactions
Protein-protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small molecule scaffolds that reproduce the relative positioning and disposition of important binding residues, termed "hotspot residues", have been shown to successfully inhibit specific protein complexes. Although this strategy has led to d...
متن کاملMultivalent helix mimetics for PPI-inhibition.
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متن کاملTowards more drug-like proteomimetics: two-faced, synthetic α-helix mimetics based on a purine scaffold.
Mimicry of two faces of an α-helix might yield more potent and more selective inhibitors of aberrant, helix-mediated protein-protein interactions (PPI). Herein, we demonstrate that a 2,6,9-tri-substituted purine is capable of disrupting the Mcl-1-Bak-BH3 PPI through effective mimicry of key residues on opposing faces of the Bak-BH3 α-helix.
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عنوان ژورنال:
- Biochemical Society transactions
دوره 36 Pt 6 شماره
صفحات -
تاریخ انتشار 2008