RESUMO
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.
Assuntos
Mimetismo Molecular , Proteínas/química , Linhagem Celular Tumoral , HumanosRESUMO
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.
Assuntos
Proteínas Proto-Oncogênicas c-mdm2/química , Proteína Supressora de Tumor p53/química , Amidas/química , Biomimética , Química Click , Humanos , Concentração Inibidora 50 , Proteína de Sequência 1 de Leucemia de Células Mieloides/química , Ligação Proteica , Mapeamento de Interação de Proteínas , Estrutura Secundária de Proteína , Proteômica/métodos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Solventes/química , Propriedades de Superfície , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína bcl-X/químicaRESUMO
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.