bims-midomi 2025-05-25 papers

J Pept Sci. 2025 Jul;31(7): e70033

Identification of Potent Cell Penetrating, Nontoxic Peptides for Inhibiting MDM2-p53 Interactions: Characterization of Anticancer Peptides via Molecular Dynamics Simulations.

Pradeep Pant, Aman Sehgal, Tushar Gupta, Pradeep Sharma.

Inhibiting MDM2-p53 interactions is a crucial therapeutic strategy in cancer treatment, as it can restore the tumor suppressor activity of p53 and inhibit tumor progression. Peptide inhibitors have shown promise in targeting this interaction; however, their optimization for in vivo use often encounters challenges, particularly in cellular uptake. The present study addresses this limitation by identifying cell-penetrating peptides (CPPs) that are predicted to be nontoxic to humans and capable of inhibiting the MDM2-p53 interaction. We utilized a comprehensive CPP database to extract unmodified peptides, focusing on those predicted to be nontoxic. Selected candidates were subjected to molecular docking followed by 500-ns all-atom explicit-solvent molecular dynamics (MD) simulations, performed in triplicates, to evaluate their binding stability and affinity with MDM2. Binding affinity calculations using MM-PBSA, AREA AFFINITY, and PRODIGY revealed that two peptides consistently exhibited stable binding to MDM2 and demonstrated higher affinity compared with the p53 reference fragment. These peptides not only maintained favorable interactions throughout the simulations but also showed strong potential to disrupt MDM2-p53 binding and reactivate p53 function. The findings highlight these peptides as promising nontoxic anticancer agents and provide a strong foundation for the development of peptide-based therapeutics targeting the MDM2-p53 interaction.

Keywords: MDM2; anticancer peptides; cell penetrating peptides; molecular dynamics simulations; p53

DOI: https://doi.org/10.1002/psc.70033

BMC Res Notes. 2025 May 17. 18(1): 221

Epstein-Barr virus nuclear antigen 1 (EBNA1) increases the expression levels of MDM2 and MDM4 genes in HeLa cells: a review on MDM2 and MDM4 roles in cancer.

Seyed Mohammad Ali Hashemi, Amir Hossein Alipour, Sima Emamifar, Ali Farhadi, Jamal Sarvari.

OBJECTIVE: Epstein-Barr virus nuclear antigen 1 (EBNA1) is a key viral protein expressed in all latency phases and EBV-associated tumors. It can modulate the expression of various host and viral genes. This study aimed to investigate the impact of EBNA1 on the expression levels of two cellular genes involved in p53 pathway regulation-MDM2 and MDM4-in HeLa cells. This investigation was conducted as part of our broader research on EBV-related oncogenic mechanisms.
RESULTS: HeLa cells were transfected with either an EBNA1-expressing plasmid or a control plasmid. Gene expression levels of MDM2 and MDM4 were analyzed using real-time PCR. The results demonstrated a statistically significant increase in MDM4 expression in EBNA1-transfected cells compared to controls (p = 0.028). Although MDM2 expression was also elevated, the difference was not statistically significant (p = 0.11). These findings suggest that EBNA1 may play a role in cervical cancer development by upregulating genes that inhibit p53 tumor suppressor activity.

DOI: https://doi.org/10.1186/s13104-025-07275-3

bioRxiv. 2025 Apr 17. pii: 2025.04.11.648454. [Epub ahead of print]

Regulation of the MDM2-p53 Nexus by a Nuclear Phosphoinositide and Small Heat Shock Protein Complex.

Jeong Hyo Lee, Mo Chen, Tianmu Wen, Richard A Anderson, Vincent L Cryns.

The tumor suppressor p53 maintains genome stability in the setting of cellular stress and is frequently mutated in cancer. The stability of p53 is regulated by its interaction with the oncoprotein MDM2, a ubiquitin E3 ligase. Recently, nuclear phosphoinositides were reported to bind and stabilize p53. Here, we report that genotoxic stress induces the type I phosphatidylinositol phosphate kinase (PIPKIα) and its product phosphatidylinositol 4,5-bisphosphate (PIP 2 ) to bind and regulate the stability and function of MDM2. Following genotoxic stress, nuclear PIPKIα binds to MDM2 to generate a complex of MDM2 and PIP 2 . PIP 2 binding to MDM2 differentially regulates the recruitment of the small heat shock proteins (sHSPs) αB-crystallin (αBC) and HSP27 to the MDM2-PIP 2 complex, acting as an on-off switch that regulates MDM2 stability, downstream targets, ubiquitination activity, and interaction with p53. Our results demonstrate an unexpected role for nuclear phosphoinositides conferring specificity to the MDM2-PIP 2 -sHSPs association. Notably, the differential engagement of αBC and HSP27 reveals that sHSPs are not merely passive chaperones but play active, selective roles in fine-tuning MDM2 function and MDM2-p53 nexus. These findings provide a novel therapeutic strategy for targeting this pathway in cancer.

DOI: https://doi.org/10.1101/2025.04.11.648454