Structural Diversity and Mechanistic Insights on Preferential Interaction of Small Molecule Ligands with i-Motif DNA Structures: Unlocking New Blueprint for Drug Discovery

Abstract

The cytosine-rich i-Motif (IM) is a four-stranded DNA structure that exemplifies the remarkable structural flexibility of nucleic acids. Stabilized under mildly acidic conditions, IMs are typically found within gene promoters and telomeres, where they are believed to play roles in regulating gene expression and cellular proliferation. The interaction between small molecules and IM DNA holds significant promise for drug discovery and therapeutic development, particularly in targeting diseases such as cancer. These interactions can help identify novel drug targets and enable precision drug delivery strategies. Beyond their therapeutic potential, IMs possess unique structural properties—such as pH-responsiveness and conformational changes upon ligand binding—that makes them highly suitable for use in biosensors. These features enable the sensitive and specific detection of target molecules, supporting a wide range of biomedical applications including disease diagnostics and theranostics. This review explores the structural characteristics of IMs, their biological relevance in drug development and delivery, as well as the mechanisms underlying their interactions with small molecules. Additionally, it discusses how the pH-sensitive nature of IM-DNA can be harnessed to design advanced biosensors and next-generation drug delivery systems.