title: 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.
authors: School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK.
authors: Valeria
authors: V
authors: Azzarito
authors: Kérya
authors: K
authors: Long
authors: Natasha S
authors: NS
authors: Murphy
authors: Andrew J
authors: AJ
authors: Wilson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects*; D017433:Protein Structure, Secondary; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011506:Proteins