Small, synthetic molecules that strongly and selectively bind to DNA in biological systems and induce specific biological responses, such as changes in gene expression, are a central goal of biomolecular compound design and synthesis research as well as therapeutic development. Control of gene expression could be accomplished directly by either inhibiting or enhancing binding of transcription factors to their DNA promoter sites. Since transcription factors themselves are frequently classified as "undruggable", targeting the DNA component of DNA-protein complexes would facilitate progress and provide an important step forward in the area. Unfortunately, there has been very limited advancement in compound designs for recognizing mixed base pair (bp) DNA promoter sequences. Heterocyclic-cationic, minor-groove binders that can selectively interact with DNA have become a valuable resource in therapeutics. These successful agents have provided proof of concept that selective recognition of the DNA minor groove with a set of modules, combined in different ways for different sequences, is possible. The combinatorial design and preparation of modular minor-groove, sequence-specific compounds that can selectively recognize GC and AT bp in more complex DNA sequences than most current agents would be a major step forward in promoter site binding. Using this approach, compounds are being prepared with H-bond donors for AT bp binding and H-bond acceptors for GC bp interactions. Conformational matching of the synthetic agents to the shape and functionality of the minor groove is critical. We now have several compounds that can selectively recognize a single GC bp with flanking AT pairs, in contrast to the traditional AT-only binding of these type compounds. The critical question at this point, which we are now addressing, is how to increase selectivity and how to extend the initial compounds to recognize longer, more complex DNA sequences with additional GC bps. By combining modular GC recognition units, we expect to prepare agents that can selectively recognize two GC bps in DNA sequences such as (A/T)m-(G/C)-(A/T)n-(G/C)-(A/T)m. The compounds should have enough flexibility to match the shape and curvature of the DNA minor groove and an appropriate length with recognition modules spaced to bind to the DNA sequence and cover a full turn of the DNA helix. The design strategy and DNA interaction results will be described.

Target-specific inhibition of transcription factors by designed, synthetic DNA ligands

255th National Meeting (2018)

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