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Characterization of a Novel DNA Minor-Groove Complex

Binh Nguyen ^*, Donald Hamelberg ^*, Christian Bailly , Pierre Colson , Jaroslav Stanek , Reto Brun ^¶, Stephen Neidle ^|| and W. David Wilson ^*

^* Department of Chemistry, Georgia State University, Atlanta, Georgia 30303 USA; INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, 59045 Lille, France; Biospectroscopy and Physical Chemistry Unit, University of Liege, 4000 Liege, Belgium; Novartis Pharma AG, CH-4002 Basel, Switzerland; ^¶ Swiss Tropical Institute, CH-4002 Basel, Switzerland; and ^|| Biomolecular Structure Unit, The School of Pharmacy, University of London, London WC1N 1AX, United Kingdom

Correspondence: Address reprint requests to W. D. Wilson, E-mail: chewdw{at}panther.gsu.edu.

Many dicationic amidine compounds bind in the DNA minor groove and have excellent biological activity against a range of infectious diseases. Para-substituted aromatic diamidines such as furamidine, which is currently being tested against trypanosomiasis in humans, and berenil, which is used in animals, are typical examples of this class. Recently, a meta-substituted diamidine, CGP 40215A, has been found to have excellent antitrypanosomal activity. The compound has a linear, conjugated linking group that can be protonated under physiological conditions when the compound interacts with DNA. Structural and molecular dynamics analysis of the DNA complex indicated an unusual AT-specific complex that involved water-mediated H-bonds between one amidine of the compound and DNA bases at the floor of the minor groove. To investigate this unique system in more detail DNase I footprinting, surface plasmon resonance biosensor techniques, linear dichroism, circular dichroism, ultraviolet-visible spectroscopy, and additional molecular dynamics simulations have been conducted. Spectrophotometric titrations of CGP 40215A binding to poly(dAT)₂ have characteristics of DNA-binding-induced spectral changes as well as effects due to binding-induced protonation of the compound linker. Both footprinting and surface plasmon resonance results show that this compound has a high affinity for AT-rich sequences of DNA but very weak binding to GC sequences. The dissociation kinetics of the CGP 40215A–DNA complex are much slower than with similar diamidines such as berenil. The linear dichroism results support a minor-groove complex for the compound in AT DNA sequences. Molecular dynamics studies complement the structural analysis and provide a clear picture of the importance of water in mediating the dynamic interactions between the ligand and the DNA bases in the minor groove.

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