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Rational design, synthesis, and biophysical characterization of a peptidic MDM2-MDM4 interaction inhibitor.
- Source :
-
Bioorganic & Medicinal Chemistry . Nov2024, Vol. 113, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
-
Abstract
- [Display omitted] • Design of a peptidic inhibitor of MDM2 dimerization (peptide 2) by means of molecular dynamics (MD) simulations. • Synthesis of peptide 2 in decamilligram scale. • Analytical characterization of peptide 2. • MST binding experiments of peptide 2 against full-length recombinant human MDM2 show a sequence-specific interaction with a K d = 19.2 ± 5.4 µM. • Bioactive peptide 2 represents an interesting lead compound to unravel MDM2 biology and develop more advanced inhibitors of MDM2-MDM4 interaction. 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PEPTIDES
*PEPTIDE synthesis
*LEAD compounds
*MOLECULAR dynamics
*UBIQUITINATION
Subjects
Details
- Language :
- English
- ISSN :
- 09680896
- Volume :
- 113
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 180175007
- Full Text :
- https://doi.org/10.1016/j.bmc.2024.117937