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Updated: May 2, 2026
Targeted DNA Methylation Analysis by Next-generation Sequencing
Published on: February 24, 2015
Targeted Inhibition of CBP/p300-NCOA3 Interactions with an α-Methylated Peptide
Aurora Silvestri1, Judit Osz1, Alexis Jouin2
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258/CNRS UMR7104/, Université de Strasbourg, 67400 Illkirch, France.
Abstract:
The CREB-binding protein (CBP) and its paralogue p300 are cellular integrators of various signaling pathways involved in various physiological functions. Together with NCOA proteins, they act as coactivators of nuclear receptors. CBP/p300 and NCOA3 are overexpressed in endocrine cancers, leading to enhanced nuclear receptor activity and promoting tumor progression through activation of oncogenes and regulation of cellular functions. Thus, targeting CBP/p300-NCOA3 has great potential for the development of antitumor agents. As a tool to disrupt disease-related protein-protein interactions, we developed the NCOA3 activation domain 1 (AD1) peptide containing noncanonical α-methylated amino acids for targeting the intrinsically disordered nuclear coactivator binding domain (NCBD) in CBP/p300. We showed that this peptide variant binds with a stronger affinity to its target proteins than the wild-type peptide and inhibits CBP/p300 acetylase activity. This peptide variant also modulates interactomes and CBP/p300-mediated gene transcription and exhibits effective antiproliferative activity in cell-based assays.
Insights
Researchers developed a novel peptide to target CBP/p300 and NCOA3, proteins overexpressed in endocrine cancers. This peptide effectively inhibits cancer cell growth by disrupting key protein interactions and gene transcription.
Area of Science:
- Molecular Biology
- Cancer Research
- Drug Discovery
Background:
- CREB-binding protein (CBP) and p300 are crucial signaling integrators and coactivators of nuclear receptors.
- Overexpression of CBP/p300 and NCOA3 in endocrine cancers promotes tumor progression.
- Targeting the CBP/p300-NCOA3 complex presents a promising therapeutic strategy.
Purpose of the Study:
- To develop a peptide-based therapeutic agent to disrupt CBP/p300-NCOA3 interactions.
- To investigate the binding affinity, inhibitory activity, and cellular effects of a novel peptide.
Main Methods:
- Design and synthesis of a modified NCOA3 activation domain 1 (AD1) peptide with noncanonical amino acids.
- Assessment of peptide binding affinity to CBP/p300's nuclear coactivator binding domain (NCBD).
- Evaluation of CBP/p300 acetylase activity inhibition, interactome modulation, and gene transcription effects.
- Cell-based assays to determine antiproliferative activity.
Main Results:
- The developed peptide variant exhibits enhanced binding affinity to CBP/p300 compared to the wild-type.
- The peptide effectively inhibits CBP/p300 acetylase activity.
- The peptide modulates protein interactions and CBP/p300-mediated gene transcription.
- Significant antiproliferative effects were observed in cell-based assays.
Conclusions:
- The novel peptide is a potent inhibitor of CBP/p300 activity and function.
- This peptide represents a promising therapeutic candidate for endocrine cancers by targeting the CBP/p300-NCOA3 pathway.
- Disruption of protein-protein interactions offers a viable strategy for developing novel anticancer agents.
