Inhibition of α-helix-mediated protein–protein interactions using designed molecules

Abstract

Inhibition of protein-protein interactions (PPIs) represents a significant challenge because it is unclear how they can be effectively and selectively targeted using small molecules. Achieving this goal is critical given the defining role of these interactions in biological processes. A rational approach to inhibitor design based on the secondary structure at the interface is the focus of much research, and different classes of designed ligands have emerged, some of which effectively and selectively disrupt targeted PPIs. This Review discusses the relevance of PPIs and, in particular, the importance of α-helix-mediated PPIs to chemical biology and drug discovery with a focus on designing inhibitors, including constrained peptides, foldamers and proteomimetic-derived ligands. In doing so, key challenges and major advances in developing generic approaches for the elaboration of PPI inhibitors are highlighted. The challenges faced in developing such ligands as drug leads--and how criteria applied to these may differ from conventional small-molecule drugs--are summarized.

Stabilization of protein–protein interactions by small molecules

“…Small molecule modulation of protein-protein interactions (PPIs) has been recognized as a promising approach in drug discovery [1][2][3]. However, in the vast majority of cases, PPI modulation is exclusively recognized as inhibition, understandably motivated by a number of wonderful success stories that have been published in recent years.…”

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

“…For that reason, it is rational to imagine that a significant population of PPIs should involve α-helices, and that a mimic of a helix recognition face could act as a small-molecular competitive inhibitor. [134][135][136][137] α-Helix mimetics can be divided into three different categories. Type I mimetics are short oligomers that strive to replicate the local topography of an α-helix.…”

“…134 Type III mimetics are non-peptidic scaffolds that mimic the surface formed by non-sequential hot-spot residues of the α-helix. [138][139][140] (Fig.…”

An α‐Helix‐Mimicking 12,13‐Helix: Designed α/β/γ‐Foldamers as Selective Inhibitors of Protein–Protein Interactions

“…As bioinspired structures, some of them have been validated as useful reagents to modulate (therapeutically important) biological processes and systems,4, 5, 6, 7, 8, 9 and others as building blocks for use in synthetic biology10, 11, 12, 13, 14 or the construction of functional materials 15, 16. A particularly fertile area is centred on the search for foldamers that mimic natural secondary structures (specifically α‐helices) and thereby act as inhibitors of protein–protein interactions (PPIs) 17, 18, 19, 20, 21. However, there is still a need to develop ligands that more effectively mimic the conformation and molecular recognition capabilities of the α‐helix.…”