Peptides Targeting RNA m6 A Methylations Influence the Viability of Cancer Cells

Abstract

N6-methyladenosine (m⁶ A) is the most abundant nucleotide modification observed in eukaryotic mRNA. Changes in m⁶ A levels in transcriptome are tightly correlated to expression levels of m⁶ A methyltransferases and demethylases. Abnormal expression levels of methyltransferases and demethylases are observed in various diseases and health conditions such as cancer, male infertility, and obesity. This research explores the efficacy of m⁶ A-modified RNA as an anticancer drug target. We discovered a 12-mer peptide that binds specifically to m⁶ A-modified RNA using phage display experiments. Our fluorescence-based assays illustrate the selected peptide binds to methylated RNA with lower micromolar affinity and inhibit the binding of protein FTO, a demethylase enzyme specific to m⁶ A modification. When cancer cell lines were treated with mtp1, it led to an increase in m⁶ A levels and a decrease in cell viability. Hence our results illustrate the potential of mtp1 to be developed as a drug for cancer.

Keywords: FTO; epitranscriptomics; m6A; peptide inhibitors; phage display.