Advancing drug targets for peptide-peptide interactions: Peptide flexibility is key in inhibiting the MDM2/p53 interaction
The search for new drug classes has gone beyond the classically druggable genome, which appears to be limited to around 1,500 proteins. One route is the development of molecules that interfere with the Protein-Protein Interactions (PPIs) that are critical to all cellular processes, such as the regulation of cell growth, DNA replication, transcriptional activation, protein folding, and transmembrane signaling. One PPI-based drug target that involves a well-defined secondary structure is the interaction between the p53 tumor suppressor, the so-called “guardian of the genome” involved in programmed cell death, and MDM2, an important negative regulator of p53. This interaction involves a “hot spot triad” of three residues, Phe19, Trp23 and Leu26, on one face of the α-helical region of p53. Mimicking this region with a peptide became the focus of a collaborative effort between University of Gothenburg, Sweden and St. Jude Children’s Research Hospital in Tennessee, USA and resulted in key insights into the balanced peptide design required to achieve effective PPI inhibition (Danelius et al, 2016).