Creation of a Synthetic Ligand for Mitochondrial DNA Sequence Recognition and Promoter-Specific Transcription Suppression

Abstract

Synthetic ligands capable of DNA sequence recognition in human mitochondria are in increasing demand because more and more studies have revealed the relation between mitochondrial genome and diseases. In this chapter, a new type of synthetic DNA-binding ligands, termed MITO-PIPs, was developed by conjugating a mitochondria-penetrating peptide with pyrrole-imidazole polyamides (PIPs). A MITO-PIP that inhibits the binding of mitochondrial transcription factor A to the light-strand promoter (LSP) triggered targeted transcriptional suppression of a downstream gene. A melting temperature analysis revealed sequence-specific DNA binding of the MITO-PIP, and mitochondrial accumulation in HeLa cells was also observed. The tunability of PIPs suggests the potential of the MITO-PIPs as potent modulators of mitochondrial gene transcription and mitochondrial DNA mutations.KeywordsMITO-PIPPyrrole–imidazole polyamideMitochondria-penetrating peptideMitochondrial DNADNA transcription inhibitor