Development of cell-penetrating peptide-based drug leads to inhibit MDMX:p53 and MDM2:p53 interactions

Philippe, Gregoire, Huang, Yen-Hua, Cheneval, Olivier, Lawrence, Nicole, Zhang, Zhen, Fairlie, David P., Craik, David J., Dantas De Araujo, Aline and Troeira Henriques, Sonia (2016) Development of cell-penetrating peptide-based drug leads to inhibit MDMX:p53 and MDM2:p53 interactions. Biopolymers - Peptide Science, 106 6: 853-863. doi:10.1002/bip.22893


Author Philippe, Gregoire
Huang, Yen-Hua
Cheneval, Olivier
Lawrence, Nicole
Zhang, Zhen
Fairlie, David P.
Craik, David J.
Dantas De Araujo, Aline
Troeira Henriques, Sonia
Title Development of cell-penetrating peptide-based drug leads to inhibit MDMX:p53 and MDM2:p53 interactions
Journal name Biopolymers - Peptide Science   Check publisher's open access policy
ISSN 1097-0282
Publication date 2016
Sub-type Article (original research)
DOI 10.1002/bip.22893
Volume 106
Issue 6
Start page 853
End page 863
Total pages 28
Place of publication Hoboken, United States
Publisher John Wiley & Sons
Collection year 2017
Language eng
Formatted abstract
The transcription factor p53 has a tumor suppressor role in leading damaged cells to apoptosis. Its activity is regulated/inhibited in healthy cells by the proteins MDM2 and MDMX. Overexpression of MDM2 and/or MDMX in cancer cells inactivates p53, facilitating tumor development. A 12-mer dual inhibitor peptide (pDI) was previously reported to be able to target and inhibit MDMX:p53 and MDM2:p53 interactions with nanomolar potency in vitro. With the aim of improving its cellular inhibitory activity, we produced a series of constrained pDI analogues featuring lactam staples that stabilize the bioactive helical conformation and fused them with a cell-penetrating peptide to increase cytosol delivery. We compared pDI and its analogues on their inhibitory potency, toxicity and ability to enter cancer cells. Overall, the results show that these analogues keep their nanomolar affinity for MDM2 and MDMX and are highly active against cancer cells. This article is protected by copyright. All rights reserved.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 17 Jun 2016, 11:10:17 EST by Susan Allen on behalf of Institute for Molecular Bioscience