Disclosing the actual efficiency of G-quadruplex-DNA–disrupting small molecules

The quest for small molecules that avidly bind to G-quadruplex-DNA (G4-DNA, or G4), so called G4-ligands, has invigorated the G4 research field from its very inception. Massive efforts have been invested to i - screen or design G4-ligands, ii - evaluate their G4-interacting properties in vitro through a series of now widely accepted and routinely implemented assays, and iii - use them as unique chemical biology tools to interrogate cellular networks that might involve G4s. In sharp contrast, only uncoordinated efforts at developing small molecules aimed at destabilizing G4s have been invested to date, even though it is now recognized that such molecular tools would have tremendous application to neurobiology as many genetic and age-related diseases are caused by an over-representation of G4s, itself caused by a deficiency of G4-resolving enzymes, the G4-helicases. Herein, we report on our double effort to i - develop a reliable in vitro assay to identify molecules able to destabilize G4s, the G4-unfold assay, and ii - fully characterize the first prototype of G4-disrupting small molecule, a phenylpyrrolcytosine (PhpC)-based G-clamp analog. ### Competing Interest Statement The authors have declared no competing interest. * § TCPP stand for : meso-tetra(4-carboxyphenyl)porphine, also known as 4,4’,4’’,4’’’-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid) or meso-Tetraphenylporphine-4,4’,4’’,4’’’-tetracarboxylic acid (Spm for spermine); TMPyP4 for : 5,10,15,20-tetrakis-[N-methyl-4-pyridyl]-21H,23H-porphyrin TEGPY for : tetra-[(ethylene glycol)-pyridyl]-porphyrin, also known as 5,10,15,20-tetrakis-[N-(2-(2-(2-methoxy)-ethoxy)-ethoxy)-ethyl-4-pyridyl]-21H,23H-porphyrin; TEGP for : tetra-[ethylene glycol]-porphyrin, also known as 5,10,15,20-tetrakis-[4-(2-(2-(2-methoxy)-ethoxy)-ethoxy)-ethyl]-21H,23H-porphyrin TArPS for : 5,10,15,20-tetrakis[3-sulfonato-4-O-[2-[2-(2-methoxy)ethoxy]ethoxy]ethylphenyl]-21H,23H-porphyrin TPPS for : 5,10,15,20-tetrakis[4-sulfonatophenyl]-21H,23H-porphyrin PhpC for : 6-phenylpyrrolocytosine (gua for guanidine).