Self-Avoiding Gamma Peptide Nucleic Acids for Selective Targeting of RNA Secondary Structures

RNA molecules play essential roles in all aspects of cellular function, but their complex secondary and tertiary structures pose significant challenges for selective targeting. Traditional antisense strategies often avoid these structured regions, focused instead on unstructured sequences. In this study, we present an enhanced Self-Avoiding Molecular Recognition System designed to selectively recognize and bind structured RNA elements, offering an alternative approach for targeting biologically relevant RNA conformations with improved specificity and selectivity. This is achieved by incorporating established self-avoidance nucleobases (t and c) along with a deazapurine series (a and g)─designed to provide greater flexibility in fine-tuning binding affinity─into a conformationally preorganized gamma peptide nucleic acid backbone. Despite possessing self-complementary arms (<i>b</i> and <i>b'</i>), the system resists self-hybridization and selectively binds to the intended stem-loop RNA target (<i>bcb'</i>). Thermal stability measurements, electrophoretic mobility assays, and mismatch specificity analyses confirm the effectiveness of this approach, offering a general strategy for targeting structured RNA with precision.