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

Area of Science:

• Molecular Biology
• Genetics
• Drug Discovery

Background:

• c-Myc is a crucial oncogene, frequently dysregulated in cancers, making it a challenging drug target.
• i-Motif (iM) DNA structures in gene promoter regions are emerging targets for gene expression modulation.
• Specific iM structures upstream of the c-Myc P1 promoter are of significant interest.

Purpose of the Study:

• To identify selective peptide ligands for the c-Myc gene promoter i-motif (iM) structure.
• To evaluate the potential of these ligands in modulating c-Myc gene expression.
• To explore their utility as chemical tools for cancer research and therapeutic development.

Main Methods:

• Phage display was employed to identify peptide ligands binding to the c-Myc iM.
• Selectivity of identified peptides for iM structures was confirmed using displacement assays and DNA melting experiments.
• Functional validation involved assessing dose-dependent changes in c-Myc gene expression in HEK293 cells using a reporter construct.

Main Results:

• Novel peptide ligands targeting the c-Myc promoter iM were successfully identified.
• Lead peptides demonstrated selective binding to iM structures over other DNA conformations.
• Two lead peptides significantly altered c-Myc gene expression in a dose-dependent manner in cellular assays.

Conclusions:

• The identified peptides serve as valuable chemical tools for in vitro manipulation of the c-Myc iM.
• These peptide leads hold potential for development into cell-permeable peptidomimetics for in vivo applications.
• Targeting c-Myc iM structures represents a promising strategy for developing novel anti-cancer therapeutics.