Non-naturally Occurring Helical Molecules Can Interfere with p53-MDM2 and p53-MDMX Protein-Protein Interactions.

We have discovered that beta-amino acid homooligomers with cis- or trans-amide conformation can fold themselves into highly ordered helices. Moreover, unlike alpha-amino acid peptides, which are significantly stabilized by intramolecular hydrogen bonding, these helical structures are autogenous conformations that are stable without the aid of hydrogen bonding and irrespective of solvent (protic/aprotic/halogenated) or temperature. A structural overlap comparison of helical cis/trans bicyclic beta-proline homooligomers with typical a-helix structure of alpha-amino acid peptides reveals clear differences of pitch and diameter per turn. Bridge-head substituents of the present homooligomers point outwards from the helical surface. We were interested to know whether such non-naturally occurring divergent helical molecules could mimic alpha-helix structures. In this study, we show that bicyclic beta-proline oligomer derivatives inhibit p53-MDM2 and p53-MDMX protein-protein interactions, exhibiting MDM2-antagonistic and MDMX-antagonistic activities.