Specific molecular recognition of mixed nucleic acid sequences: An aromatic dication that binds in the DNA minor groove as a dimer

Abstract

Phenylamidine cationic groups linked by a furan ring (furamidine) and related compounds bind as monomers to AT sequences of DNA. An unsymmetric derivative (DB293) with one of the phenyl rings of furamidine replaced with a benzimidazole has been found by quantitative footprinting analyses to bind to GC-containing sites on DNA more strongly than to pure AT sequences. NMR structural analysis and surface plasmon resonance binding results clearly demonstrate that DB293 binds in the minor groove at specific GC-containing sequences of DNA in a highly cooperative manner as a stacked dimer. Neither the symmetric bisphenyl nor bisbenzimidazole analogs of DB293 bind significantly to the GC containing sequences. DB293 provides a paradigm for design of compounds for specific recognition of mixed DNA sequences and extends the boundaries for small molecule-DNA recognition. O rganic cations that bind in the DNA minor groove have biological activities that range from anti-opportunistic infection to anticancer properties (1-5). Such compounds have also provided a wealth of fundamental information about nucleic acid recognition properties, and they continue to be important models in the study of nucleic acid complexes (1, 2, 6-8). Netropsin ( Fig. 1) was the first minor-groove-binding compound crystallized with a B-form DNA, and the structure of the complex provided clear suggestions about the molecular basis for AT base pair sequence-specific recognition (9). The structure also lead to proposals by the Dickerson and Lown groups for minor-groove binding netropsin analogs, lexitropsins, that could specifically recognize GC base pairs and could, thus, have extended sequence recognition capability (10-12). Initial efforts in the design of analogs of netropsin that could recognize GC base pairs, however, yielded compounds of limited specificity. A breakthrough in this area occurred with the discovery that the monocationic relative of netropsin, distamycin ( Fig. 1), could bind into the minor groove of some AT sequences of DNA as a stacked, antiparallel dimer (7,13,14). Replacement of pyrrole groups in distamycin by imidazole provided lexitropsins with improved GC recognition specificity through dimer complexes, and current design efforts in the pyrrole-imidazole polyamide system have reached a high level of success (15-18). With recent developments by the Dervan group, AT and TA as well as GC and CG base pairs can now be effectively distinguished in DNA sequences by polyamides (15-18).Interestingly, the polyamide system is the only one of the well known minor-groove binding motifs that has yielded conclusive evidence for formation of the stacked-dimer recognition unit, although recent evidence indicates that some monocationic cyanine dyes can form an array of stacked dimers in the DNA minor groove (19). No dications have been found to form the stacked-dimer recognition motif. Netropsin, the first minorgroove-binding agent to be characterized in detail and a dicationic relative of the monocation distamycin (Fig. 1), for example, does n...

A novel dicationic polyamide ligand binds in the DNA minor groove as a dimer

“…It has been shown previously that a benzimidazolecontaining dicationic compound (without amide bond linkage) can form a dimer in the DNA minor groove [12,13]. Our results provide evidence of the ¢rst dicationic polyamide that is capable of dimerizing in the minor groove.…”

“…On a local structural level, the nuclear magnetic resonance (NMR) structure of the distamycin homodimer bound to 5P-dCGCAAATTGCG-3P [11] showed that the minor groove has to be widened signi¢cantly to accommodate two side-by-side distamycin molecules. More recently, Wilson and co-workers demonstrated that a small non-peptide dication also can dimerize upon binding to the DNA minor groove [12,13].…”

Antiparasitic compounds that target DNA

“…Diamidines that recognize DNA sequences that contain GC base pairs, including majority GC sequences, have now been described [76][77][78][79][80]. In addition we realize that the curved shape of diamidines is one option for binding but is not a requirement.…”

Detection of Inhibition of Bovine Viral Diarrhea Virus by Aromatic Cationic Molecules

“…Since related compounds have been identified as protease inhibitors (14,39) and helicase inhibitors (32) and have been shown to be effective in binding to nucleic acids (24,40), multiple mechanisms of action might be employed by the nontoxic antiviral compounds reported here. Mechanisms of action of other anti-BVDV agents include inhibition of viral RNA-dependent RNA polymerase (2) and of ␣-glucosidase, which results in the misfolding of viral proteins (30).…”