Translating G-quadruplex ligands from bench to bedside: a Stephen Neidle’s legacy

DNA and RNA G-quadruplexes (G4s) are alternative nucleic acid structures that can fold from thousands of guanine (G)-rich sequences in the genome and transcriptome of human cells. Invaluable information about the prevalence and functional relevance of G4s has been gained using G4-specific small molecules (or G4 ligands): cell-based ligand perturbation experiments have indeed provided readouts that were astutely exploited to gain accurate and reliable insights into G4 biology. As a consequence, these investigations have opened the way towards using G4 ligands as drug candidates to fight against genetic diseases, chiefly cancers. This quite active field of research, at the crossroads between chemical biology and medicinal chemistry, thus entirely relies on specific G4 ligands. The greatest contribution to the G4 ligand field is undoubtedly to be attributed to Prof. Stephen Neidle (London, UK). He was indeed the first to design and synthesize G4-interacting compounds, fully characterize their interaction with their G4 targets, and study them in cells with an eye towards benefiting from the central position of G4s in cellular biology to use them as new targets for therapeutic intervention. This review provides an overview of the developments that the G4 ligand field has experienced since the initial impetus provided by Prof. Neidle in 1997, and depicts the trajectories taken by some of them to become ever smarter molecular tools (chemical biology) or drug candidates under clinical assessment (medicinal chemistry).