Design of a novel MDM2 binding peptide based on the p53 family.

p53 is a major tumor suppressor protein, that binds to, and is negatively regulated by MDM2. In tumors overexpressing MDM2, p53 function can be rescued through the disruption of the MDM2-p53 interactions by small molecules and peptides. It is known that MDM2 also binds p73 but not p63, the two homologues of p53. We dissect the structural and energetic reasons underlying this discrimination and have identified a peptide that is intrinsically less helical than p53 and yet has a higher affinity for MDM2. The increased disorder has been introduced by localizing a cationic residue in between two anionic residues, imparting a degree of frustration to the system. In addition, the introduction of a bulkier hydrophobic group towards the centre of the peptide enables the peptide to adapt a bound conformation that on the one hand is most strained, and yet enables the peptide to straddle the largest surface of MDM2, amongst all the peptides. Computations also reveal that this peptide is a dual inhibitor, binding also to MDMX. The computed affinity of the new peptide has been validated against MDM2 using fluorescence-based thermal shift assays.