title: Recognition and discrimination of DNA quadruplexes by acridine-peptide conjugates.
abstract: We have explored a series of trisubstituted acridine-peptide conjugates for their ability to recognize and discriminate between DNA quadruplexes derived from the human telomere, and the c-kit and N-ras proto-oncogenes. Quadruplex affinity was measured as the peptide sequences were varied, together with their substitution position on the acridine, and the identity of the C-terminus (acid or amide). Surface plasmon resonance measurements revealed that all compounds bound to the human telomeric quadruplex with sub-micromolar affinity. Docking calculations from molecular modelling studies were used to model the effects of substituent orientation and peptide sequence. Modelling and experiment were in agreement that placement of the peptide over the face of the acridine is detrimental to binding affinity. The highest degrees of selectivity were observed towards the N-ras quadruplex by compounds capable of forming simultaneous contacts with their acridine and peptide moieties. The ligands that bound best displayed quadruplex affinities in the 1-5 nM range and at least 10-fold discrimination between the quadruplexes studied.
authors.affiliation: University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Redman
authors.forename: J M
authors.initials: JM
authors.lastname: Granadino-Roldán
authors.forename: James A
authors.initials: JA
authors.lastname: Schouten
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladame
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Reszka
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.forename: Shankar
authors.initials: S
authors.lastname: Balasubramanian
mesh_terms: D000166:Acridines / Q000737:chemistry*; D019921:Biotinylation; D004247:DNA / Q000737:chemistry; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D016615:Telomere / Q000648:ultrastructure; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000166:Acridines; D008024:Ligands; D010455:Peptides; D004247:DNA; D018631:ras Proteins