Work

Affinity-selected peptide ligands specifically bind i-motif DNA and modulate c-Myc gene expression

Year: 2025

Type: article

Abstract: c-Myc is an oncogene that is dysregulated in ∼70% of cancers. Its multifaceted function complicates effective drug targeting of the protein. i-Motif (iM) DNA structures in gene promoter regions have gained attention for their potential role in the modulation of gene expression. These include the iM formed by the cytosine-rich sequence which lies upstream of the key P1 promoter of the c-Myc gene. Currently, selective ligands interacting with iM structures are limited. Here, peptide ligands for the iM from the promoter of c-Myc were identified via phage display. Hit peptides were filtered for selective binding to iM structures over other DNA structures using displacement assays and DNA melting experiments. Two lead peptides were found to produce dose-dependent changes in c-Myc gene expression after delivery into HEK293 cells expressing a c-Myc luciferase reporter construct. These leads may be used as chemical tools for the manipulation of c-Myc iM in vitro and have the potential to be developed into cell-permeable peptidomimetics for delivery in vivo.

Source: Nucleic Acids Research

DOI: 10.1093/nar/gkaf1052