Issue 12, 2023

Stitched peptides as potential cell permeable inhibitors of oncogenic DAXX protein

Abstract

DAXX (Death Domain Associated Protein 6) is frequently upregulated in various common cancers, and its suppression has been linked to reduced tumor progression. Consequently, DAXX has gained significant interest as a therapeutic target in such cancers. DAXX is known to function in several critical biological pathways including chromatin remodelling, transcription regulation, and DNA repair. Leveraging structural information, we have designed and developed a novel set of stapled/stitched peptides that specifically target a surface on the N-terminal helical bundle domain of DAXX. This surface serves as the anchor point for binding to multiple interaction partners, such as Rassf1C, p53, Mdm2, and ATRX, as well as for the auto-regulation of the DAXX N-terminal SUMO interaction motif (SIM). Our experiments demonstrate that these peptides effectively bind to and inhibit DAXX with a higher affinity than the known interaction partners. Furthermore, these peptides release the auto-inhibited SIM, enabling it to interact with SUMO−1. Importantly, we have developed stitched peptides that can enter cells, maintaining their intracellular concentrations at nanomolar levels even after 24 hours, without causing any membrane perturbation. Collectively, our findings suggest that these stitched peptides not only serve as valuable tools for probing the molecular interactions of DAXX but also hold potential as precursors to the development of therapeutic interventions.

Graphical abstract: Stitched peptides as potential cell permeable inhibitors of oncogenic DAXX protein

Supplementary files

Article information

Article type
Paper
Submitted
13 Aug 2023
Accepted
25 Sep 2023
First published
11 Oct 2023
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2023,4, 1096-1110

Stitched peptides as potential cell permeable inhibitors of oncogenic DAXX protein

C. Jelinska, S. Kannan, Y. Frosi, S. R. Ramlan, F. Winnerdy, R. Lakshminarayanan, C. W. Johannes, C. J. Brown, A. Phan, D. Rhodes and C. S. Verma, RSC Chem. Biol., 2023, 4, 1096 DOI: 10.1039/D3CB00149K

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements