Expanding DNA Sequence Recognition with Minor Groove Binders

Abstract

Heterocyclic cations are taken up into cells and can target the DNA minor groove and they offer a potential method to control cellular gene expression. A limitation of these compounds is their limited DNA sequence recognition capability and a key goal of our research has been to expand their ability to target selected DNA sequences. The results show that formation of minor groove stacked-dimer complexes is an effective way to enhance the specificity and expand the range of applications of the compounds. The discovery of the diamidine DB293 (phenyl-furan-benzimidazole), the first dication to recognize DNA as a stacked dimer in the minor groove, provided an opening to this effort. This approach, filling the minor groove with two stacked heterocyclic cations, provides an opportunity to interact with wider minor grooves which are difficult to recognize by a single molecule. Dimer recognition of DNA by these compounds is highly sensitive to compound structure as well as the target sequence. DB1242 (phenyl-pyrimidine-phenyl), a linear dication, is able to stack as a dimer in a GC rich sequence forming a curved complex which matches to the shape of minor groove. This is a example of how a linear compound with chemical functionalities in an optimum position can form intra as well as intermolecular interactions with DNA. Our finding that TTAA sequences are difficult to target, can be selectively recognized by stacked minor groove dimmers opens a new way to interact with that sequence. These investigations indicate that compound design tools can be used to obtain new types of specific binding to DNA. Supported by NIAID grant AI64200.