Systematic Evaluation of Benchmark G4 Probes and G4 Clinical Drugs using three Biophysical Methods: A Guideline to Evaluate Rapidly G4‐Binding Affinity

Author:

Laigre E.12,Bonnet H.3,Beauvineau C.12,Lavergne T.3ORCID,Verga D.12ORCID,Defrancq E.3ORCID,Dejeu J.34ORCID,Teulade‐Fichou M.‐P.12ORCID

Affiliation:

1. CNRS UMR9187 INSERM U1196 Institut Curie PSL Research University F-91405 Orsay France

2. CNRS UMR9187 INSERM U1196 Université Paris-Saclay F-91405 Orsay France

3. DCM UMR 5250 Univ. Grenoble Alpes CNRS 570 Rue de la Chimie 38000 Grenoble France

4. SUPMICROTECH Université Franche-Comté CNRS Institut FEMTO-ST 25000 Besançon France

Abstract

AbstractG‐quadruplex DNA structures (G4) are proven to interfere with most genetic and epigenetic processes. Small molecules binding these structures (G4 ligands) are invaluable tools to probe G4‐biology and address G4‐druggability in various diseases (cancer, viral infections). However, the large number of reported G4 ligands (>1000) could lead to confusion while selecting one for a given application. Herein we conducted a systematic affinity ranking of 11 popular G4 ligands vs 5 classical G4 sequences using FRET‐melting, G4‐FID assays and SPR. Interestingly SPR data globally align with the rankings obtained from the two semi‐quantitative assays despite discrepancies due to limits and characteristics of each assay. In the whole, PhenDC3 emerges as the most potent binder irrespective of the G4 sequence. Immediately below PDS, PDC‐360A, BRACO19, TMPyP4 and RHPS4 feature strong to medium binding again with poor G4 topology discrimination. More strikingly, the G4 drugs Quarfloxin, CX5461 and c‐PDS exhibit weak affinity with all G4s studied. Finally, NMM and Cu‐ttpy showed heterogeneous behaviors due, in part, to their physicochemical particularities poorly compatible with screening conditions. The remarkable properties of PhenDC3 led us to propose its use for benchmarking FRET‐melting and G4‐FID assays for rapid G4‐affinity evaluation of newly developed ligands.

Funder

LABoratoires d’EXcellence ARCANE

Publisher

Wiley

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