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bioRxiv · 10.1101/2025.05.30.656635

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

Rosonovski, S. S.·Guneri, D.·King, J. J.·Morris, C. J.·Waller, Z. A. E.
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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 DNA structures in gene promotor regions have gained attention for their potential role in modulation of gene expression. These include the i-motif formed by the cytosine-rich sequence that lies upstream of the key P1 promotor of the c-Myc gene. Currently, selective ligands interacting with i-motif structures are limited. Here, peptide ligands for the i-motif from the promoter of c-Myc were identified via phage display. Hit peptides were filtered for selective binding to i-motif structures over other DNA structures using displacement assays and DNA melting experiments. Two lead peptides were found to produce dose-dependent changes on 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 i-motif in vitro and have potential to be developed into cell-permeable peptidomimetics for delivery in vivo. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/656635v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@18a4e9aorg.highwire.dtl.DTLVardef@12e72b0org.highwire.dtl.DTLVardef@6ba866org.highwire.dtl.DTLVardef@1fcd338_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Rosonovski, S. S., Guneri, D., King, J. J., Morris, C. J., Waller, Z. A. E.. 2025-05-31. Affinity-selected peptide ligands specifically bind i-motif DNA and modulate c-Myc gene expression. https://doi.org/10.1101/2025.05.30.656635

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