Article (Scientific journals)
Design of DNA minor groove binding diamidines that recognize GC base pair sequences: a dimeric-hinge interaction motif.
Munde, Manoj; Ismail, Mohamed A; Arafa, Reem et al.
2007In Journal of the American Chemical Society, 129 (44), p. 13732-43
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Keywords :
Amino Acid Motifs; Base Pairing; Base Sequence; Binding Sites; Biosensing Techniques/methods; Calorimetry; DNA/chemistry; DNA Footprinting/methods; Deoxyribonuclease I/chemistry; Hydrogen Bonding; Models, Molecular; Molecular Structure; Pentamidine/chemistry; Sensitivity and Specificity; Surface Plasmon Resonance/methods; Thermodynamics
Abstract :
[en] The classical model of DNA minor groove binding compounds is that they should have a crescent shape that closely fits the helical twist of the groove. Several compounds with relatively linear shape and large dihedral twist, however, have been found recently to bind strongly to the minor groove. These observations raise the question of how far the curvature requirement could be relaxed. As an initial step in experimental analysis of this question, a linear triphenyl diamidine, DB1111, and a series of nitrogen tricyclic analogues were prepared. The goal with the heterocycles is to design GC binding selectivity into heterocyclic compounds that can get into cells and exert biological effects. The compounds have a zero radius of curvature from amidine carbon to amidine carbon but a significant dihedral twist across the tricyclic and amidine-ring junctions. They would not be expected to bind well to the DNA minor groove by shape-matching criteria. Detailed DNase I footprinting studies of the sequence specificity of this set of diamidines indicated that a pyrimidine heterocyclic derivative, DB1242, binds specifically to a GC-rich sequence, -GCTCG-. It binds to the GC sequence more strongly than to the usual AT recognition sequences for curved minor groove agents. Other similar derivatives did not exhibit the GC specificity. Biosensor-surface plasmon resonance and isothermal titration calorimetry experiments indicate that DB1242 binds to the GC sequence as a highly cooperative stacked dimer. Circular dichroism results indicate that the compound binds in the minor groove. Molecular modeling studies support a minor groove complex and provide an inter-compound and compound-DNA hydrogen-bonding rational for the unusual GC binding specificity and the requirement for a pyrimidine heterocycle. This compound represents a new direction in the development of DNA sequence-specific agents, and it is the first non-polyamide, synthetic compound to specifically recognize a DNA sequence with a majority of GC base pairs.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Munde, Manoj
Ismail, Mohamed A
Arafa, Reem
Peixoto, Paul 
Collar, Catharine J
Liu, Yang
Hu, Laixing
David-Cordonnier, Marie Hélène
Lansiaux, Amelie
Bailly, Christian
Boykin, David W
Wilson, W David
Language :
English
Title :
Design of DNA minor groove binding diamidines that recognize GC base pair sequences: a dimeric-hinge interaction motif.
Publication date :
2007
Journal title :
Journal of the American Chemical Society
ISSN :
0002-7863
eISSN :
1520-5126
Publisher :
American Chemical Society, Washington, United States - District of Columbia
Volume :
129
Issue :
44
Pages :
13732-43
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 03 March 2011

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