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

Abstract

We have discovered that β-amino acid homooligomers with cis-or trans-amide conformation can fold themselves into highly ordered helices. Moreover, unlike α-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 β-proline homooligomers with typical α-helix structure of α-amino acid peptides reveals clear differences of pitch and diameter per turn. Bridgehead 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 α-helix structures. In this study, we show that bicyclic β-proline oligomer derivatives inhibit p53-MDM2 and p53-MDMX protein-protein interactions, exhibiting MDM2-antagonistic and MDMX-antagonistic activities.

Elaboration of Non-naturally Occurring Helical Tripeptides as p53–MDM2/MDMX Interaction Inhibitors

“…Our initial screening of a library of diverse Abh-AA oligomers revealed that homooligomers as short as the trimer, with a p-bromobenzoyl group at the N-terminal position, showed potent MDM2-and MDMX-antagonistic activities. 9) This result suggested that the hydrophobic surface of the tAbh-AA helix fits well into the MDM2 pocket, blocking the interaction with p53. Due to their high hydrophobicity and relatively small molecular weight (M.W.…”

Hesperidin Inhibits the p53-MDMXInteraction-Induced Apoptosis of Non-Small-Cell Lung Cancer and Enhances the Antitumor Effect of Carboplatin

“…Protein-protein interaction (PPI) is an important structural point in the process of tumor formation and development and is also one of the di culties in targeted tumor therapy [10]. e development of PPI inhibitors for MDMX and P53 provides a new research direction for the treatment of NSCLC [11,12].…”

Interplay of Pyrrolidine Units with Homo/Hetero Chirality and CF3–Aryl Substituents on Secondary Structures of β-Proline Tripeptides in Solution

“…Folding of the PPII-like helix was suggested for β-proline oligomers, while substitution and bridging of the pyrrolidine ring provided a certain extent of conformational control . Peptidomimetic properties of bicyclic β-proline homooligomeric derivatives allowed inhibition of p53/MDM2 and p53/MDMX interactions …”

“…16 Peptidomimetic properties of bicyclic β-proline homooligomeric derivatives allowed inhibition of p53/MDM2 and p53/MDMX interactions. 17 Recently, we introduced a new protecting-group-free method to synthesize β-proline oligopeptides formally made of chiral 5-arylpyrrolidine-2,4-dicarboxylate structural units. 18,19 A formal chain elongation of β-proline oligopeptidic backbone was performed by step-by-step methodology based on 1,3-dipolar cycloaddition of azomethyne ylides.…”