Rational design, synthesis, and biophysical characterization of a peptidic MDM2-MDM4 interaction inhibitor.

In recent years, the restoration of p53 physiological functions has become an attractive therapeutic approach to develop novel and efficacious cancer therapies. Among other mechanisms, the oncosuppressor protein p53 is functionally regulated by MDM2 through its E3 ligase function. MDM2 promotes p53 ubiquitination and degradation following homodimerization or heterodimerization with MDM4. Recently, we discovered Pep3 (1, Pellegrino et al., 2015), a novel peptidic inhibitor of MDM2 dimerization able to restore p53 oncosuppressive functions both in vitro and in vivo. In this work, we were able to identify the key interactions between peptide 1 and MDM2 RING domain and to design peptide 2, a truncated version of 1 that is still able to bind MDM2. Integrating both computational and biophysical techniques, we show that peptide 2 maintains the conserved peptide 1-MDM2 interactions and is still able to bind to full-length MDM2.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Antonio Macchiarulo reports financial support was provided by Consorzio Interuniversitario Nazionale Metodologie e Processi Innovativi di Sintesi (C.I.N.M.P.I.S). Fabiola Moretti reports financial support was provided by the Italian Association for Cancer Research Grant (AIRC IG 21814). Andrea Temperini reports financial support was provided by Consorzio Interuniversitario Nazionale Metodologie e Processi Innovativi di Sintesi (C.I.N.M.P.I.S). Antonio Macchiarulo has patent #IT102023000015816 pending to CNR, Via del Fosso di Fiorano 64, 00143 Roma. Fabiola Moretti has patent #IT102023000015816 pending to CNR, Via del Fosso di Fiorano 64, 00143 Roma. Andrea Temperini has patent #IT102023000015816 pending to CNR, Via del Fosso di Fiorano 64, 00143 Roma. Marco Ballarotto has patent #IT102023000015816 pending to CNR, Via del Fosso di Fiorano 64, 00143 Roma. Sonia Valentini has patent #IT102023000015816 pending to CNR, Via del Fosso di Fiorano 64, 00143 Roma. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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