It should be possible to control targeted gene expression using sequence-specific DNA-binding small molecules. Instead of targeting the major groove where many proteins bind, insertion of minor groove binding compounds (MGB) can induce changes in the global DNA conformation, allosterically inhibiting DNA-protein interactions necessary for transcriptional processes. Many MGBs share a commonality for high specificity of contiguous AT-base pairs (bp), but show little preference over alternating AT or A-tract sequences. Fewer compounds show selectivity for mixed and GC-containing sequences. Several new, synthetic heterocyclic diamidine compounds recognize target sequences through binding of two adjacent sites in the minor groove. These �two-site� compounds show increased specificity and have the ability to recognize one or more GC bps. A series of combinatorial methods have been employed to better characterize and understand specificity for mixed sequences. Electrospray ionization mass spectrometry (ESI-MS) was used to detect MGB-DNA interactions among multiple DNA sequences and two-site compounds. Enzymatic-based approaches provide an independent method to identify binding sites. These methods, for example, probe the effects of compound recognition due to differences in DNA minor groove geometry between quite similar target sites (ATATGATAT verses AATTGAATT).  With this combination of techniques, we have identified compounds which can recognize mixed-base pair sequences, ultimately leading to the advancement of more promising therapeutics.

Understanding sequence-specific binding of novel minor groove binders through combinatorial approaches

247th National Meeting (2014)

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