Highly Preorganized Artificial Phosphoesterases

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With this award the Organic and Macromolecular Chemistry Program continues its support for the work of Dr. Eric V. Anslyn in the Department of Chemistry at the University of Texas at Austin. The work aims to prepare artificial phosphoesterase enzymes capable of cleaving RNA with rates and selectivities rivaling those of the natural enzymes. The approach involves systematic structural variations around a rigid hexasubstituted benzene core with attached electrophilic Zn(+2) and guanidinium cation sites. Cooperativity between metal ion sites and between metal ions and guanidinium will be investigated using kinetics, measurements of equilibrium binding constants, pH titrations, and crystallography.Artificial enzymes which can cleave DNA will be developed by making small tight cavities in which DNA can form at least four and as many as six hydrogen bonds to positively charged zinc or guanidinium ions. The keys to these new catalysts are the large number of potential binding interactions and the rigidity of the cavity walls. If effective catalysts can be developed they would be useful in gene therapy. The PI has a record of being an excellent teacher and research mentor, and has helped a number of female graduate students to go on to get PhDs.