Researchers created stitched peptides that enter cells and inhibit the cancer-linked DAXX protein with higher affinity than its natural binding partners, maintaining nanomolar concentrations inside cells for over 24 hours.
Nanomolar levels maintained 24+ hoursThe stitched peptides entered cells and maintained nanomolar intracellular concentrations for at least 24 hours — a critical benchmark for therapeutic utility — without disrupting cell membranes.
What the researchers found
Novel stapled/stitched peptides were designed to target the N-terminal helical bundle of the DAXX oncoprotein, binding with higher affinity than DAXX's known natural interaction partners (Rassf1C, p53, Mdm2, ATRX). The peptides effectively inhibited DAXX and released its auto-inhibited SUMO interaction motif, enabling it to bind SUMO-1. Critically, the stitched peptides entered cells and maintained nanomolar intracellular concentrations for at least 24 hours without disrupting cell membranes.
Why it matters
DAXX is upregulated in many common cancers and its suppression reduces tumor progression, but it has been considered difficult to drug because its critical interactions occur inside cells. These stitched peptides are the first reported cell-permeable inhibitors targeting DAXX, demonstrating that this oncoprotein is druggable and opening a new avenue for cancer therapy development.
How the study worked
Using structural information about the DAXX N-terminal helical bundle domain, the researchers designed stapled and stitched peptide variants targeting the surface where multiple protein partners bind. Binding affinity was measured and compared to known DAXX interaction partners. The effect on DAXX's auto-inhibited SUMO interaction motif was assessed. Cell permeability was evaluated by measuring intracellular peptide concentrations over 24 hours, and membrane integrity was confirmed to rule out non-specific membrane disruption.
Who was studied
In vitro biochemical and cell-based experiments — no human or animal subjects
What this study cannot tell us
This is an early-stage drug development study focused on in vitro characterization — no in vivo animal models or efficacy data were included. While the peptides enter cells at nanomolar levels, their ability to suppress DAXX-dependent tumor growth in living organisms has not been demonstrated. The therapeutic window between DAXX inhibition and normal cellular function is not yet characterized. Specific cancer cell line data and dose-response relationships are not reported in the abstract.
How to read the evidence
This is a preclinical proof-of-concept study demonstrating in vitro binding, functional inhibition, and cell permeability of novel peptides. While the biochemical data is strong, there is no in vivo efficacy data or toxicity profiling, placing this firmly in the early discovery stage.
When this study was published
Published in 2023, this is a recent contribution to the growing field of stitched/stapled peptide therapeutics. DAXX-targeting peptides are at an early stage of development with no clinical candidates yet.
The bigger picture
Many cancer-driving proteins like DAXX have been considered 'undruggable' because they function inside cells and interact through broad protein surfaces rather than small pockets that traditional drugs can fill. Stitched peptides — an evolution of stapled peptides with additional cross-links for stability — represent a growing class of molecules that can tackle these challenging targets. This work adds DAXX to the list of oncoproteins that may be addressable through peptide-based approaches.
Questions still open
- Can these stitched peptides suppress DAXX-dependent tumor growth in animal models of cancer?
- What is the selectivity of these peptides for DAXX over other structurally similar proteins, and are there off-target effects?
- Could these peptides be optimized for oral bioavailability or must they be delivered by injection?
Common questions
What makes a peptide 'stitched' and why does it matter?
Why is the DAXX protein important in cancer?
Read the original research
Stitched peptides as potential cell permeable inhibitors of oncogenic DAXX protein.
RSC chemical biology, 4(12), 1096-1110
Citation
Jelinska, Clare; Kannan, Srinivasaraghavan; Frosi, Yuri; Ramlan, Siti Radhiah; Winnerdy, Fernaldo; Lakshminarayanan, Rajamani; Johannes, Charles W; Brown, Christopher J; Phan, Anh-Tuan; Rhodes, Daniela; Verma, Chandra S. (2023). Stitched peptides as potential cell permeable inhibitors of oncogenic DAXX protein.. RSC chemical biology, 4(12), 1096-1110. https://doi.org/10.1039/d3cb00149k