Precision/Locus-Selective G-Quadruplex Stabilization as the Next Medicinal Chemistry Challenge

Abstract G-quadruplexes (G4s) are druggable nucleic acid structures implicated in gene regulation and disease, but translating G4 ligands into medicines remains difficult because affinity for shared G-tetrad features can produce broad target engagement and obscure locus-specific mechanisms. This Perspective distinguishes topology selectivity from true genomic or transcriptomic selectivity and examines emerging strategies that add sequence addressability or induced proximity to G4 pharmacology. We discuss CRISPR-guided G4 modulation, G4-ligand-oligonucleotide conjugates, and RNA-targeting chimeras, together with earlier sequence-directed polyamide approaches and selective small-molecule precedents. We also consider medicinal chemistry parameters including ligand exit vector, linker architecture, charge, subcellular access, residence time, and off-target burden, and propose a staged validation workflow from biophysical profiling to locus-specific perturbation. We argue that programmable approaches are valuable complements to, rather than replacements for, optimized small-molecule G4 ligands.