RUI: Exploring Shape-selective Binding of the DNA Major Groove by Haiprin bis(diarylmethylene)Hydrazides

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With this award, the Chemistry of Life Processes Program of the Chemistry Division is funding Dr. Thomas Minehan from California State University-Northridge to investigate how tightly a set of hairpin bis(diarylmethylene)-hydrazide compounds bind to the DNA major groove and thereby potentially provide new tools to control when and at what levels genes are expressed. Nature's transcription factors are proteins that control when genes are turned on in cells by recognizing and binding DNA sequences in the major groove of the double-helix. Compounds that compete against transcription factor binding can thus be used to control genes that may be out of control. The molecules being constructed herein are to recognize regions in the DNA that are widened, mimicking the shape of the double-helix when proteins bind. Efforts to develop molecules that recognize DNA shape-selectively represent important new exploratory directions in chemistry and chemical biology. Success here could lead to a new class of tailored synthetic agents that modulate gene expression. The research provides valuable training at the interface of organic and biological chemistry to both undergraduate and graduate students. In addition, a new course and teaching resources are being developed to increase the appreciation of chemistry-related fields by non-science students.There is great need to develop new chemical scaffolds for sequence-specific major-groove binders. Peptide-tethered bis(diarylmethylene)-hydrazides are sterically bulky small molecules with defined distances between positively charged dimethylamino groups. Varying the tether length and aromatic surface area of these molecules allows the design of ligands with well defined distances between the projected positive charges so as to contact the negatively charged phosphate groups on opposite sides of expanded DNA major groove. Four hydrazide ligands possessing varying N-N spans will be synthesized and their DNA binding affinity and sequence selectivity evaluated using fluorescent intercalator displacement assays and isothermal titration calorimetry. These studies, together with X-ray crystallographic data on select DNA-ligand complexes, will be used to achieve optimal ligand structures for sequence-selective binding. Finally, an electrophoretic mobility shift assay is to be utilized to assess the ability of the ligands to selectively inhibit the binding of transcription factors to their target nucleic acid sequences, thus shedding light on the therapeutic and biotechnological promise of this class of compounds.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.