Targeting G‐Rich lncRNA and its Structural Polymorphism with Selective G‐Quadruplex Ligands: An NMR Study

Long noncoding RNAs (lncRNAs) play essential regulatory roles, often mediated by complex structural elements such as RNA G‐quadruplexes (rGQs). While ligand interactions with DNA G‐quadruplexes (dGQs) have been extensively studied, for rGQs remain less explored. Here, we studied the SL15P RNA oligonucleotide derived from the REG1CP lncRNA, which adopts a parallel rGQ structure in equilibrium with a hairpin (Hp). A set of 12 small molecules, previously known for their ability to make complex with dGQs, was tested for their ability to bind and stabilize the SL15P rGQ. Using NMR spectroscopy, we analyzed complex formation and assessed whether these ligands could promote rGQ folding under conditions where the Hp structure is favored. Melting experiments with circular dichroism (CD) quantified the thermal stabilization induced by ligand binding. Our results show that ligands known to target dGQs exhibit different behaviors toward rGQs. Among the tested compounds, 360A, PhenDC3, and PDS proved to be the most effective, as they induced well‐defined complex formation and significant stabilization of the SL15P rGQ. PhenDC3 showed evidence of a dual binding interaction. This study emphasizes that the binding of ligands to rGQs can be highly variable and supports the rational design of selective compounds for therapeutic purposes.