Cell viable rationally designed organic small molecules which bind specific DNA sequences with the ability to interfere with protein-DNA interfaces would be useful in control of gene expression. To target the regulatory elements of eukaryotic genes, knowledge of the preferred binding of the designed compounds and their binding affinity and kinetics with each site can lead us towards the goal of gene regulation. After our success with sequence specific mixed DNA recognition by aza-benzimidazole substituted diamidines, the next required step is to design an additional heterocyclic amidines for GC base pair recognition. Such molecules must be based on lone pair electron availability of hetero atoms with flexible linkers. To accomplish this, a library of compounds with symmetrical bis-benzimidazoles connected through different linkers has been synthesized. The compounds of interest were surveyed against a broad spectrum of mixed DNA sequences by using thermal denaturation (ΔTm), circular dichroism (CD), biosensor-surface plasmon resonance (SPR), mass spectrometry (MS), DNase I footprinting, and molecular modeling methods. Extensive studies have revealed that these rationally designed molecules display high binding sequence specificity when binding to the minor groove of mixed DNA sequences. Pyridyl-linked bis-benzimidazole molecules show very strong binding potency with very slow dissociation kinetics specifically at GC base pair containing mixed DNA sequences. Based on these results, another module for recognition of complex DNA sequences by synthetic organic molecules is now available (supported by NIH GM111749).

Progress in design of programmable DNA minor groove agents for recognition of mixed sequences

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.