Metal Fluoride-based tools for understanding phosphodiesterases

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Recently, we developed a range of inorganic metallofluoride compounds that act as transition state analogues (TSAs) for enzymes that transfer phosphate monoesters. Arguably, they represent the most accurate TSAs known for any biocatalyst [1-3]. We now intend to explore the development and application of related compounds that will similarly transform the understanding of catalysis by and inhibition of enzymes that transfer phosphate diesters. This class of enzyme includes a multitude of members of exceedingly high value. It contains many of the enzymes that manipulate and maintain DNA and RNA across all kingdoms of life, including a wealth of therapeutic targets (from antiviral to anticancer) and enzymes that underpin molecular and synthetic biology (from polymerases to restriction enzymes). We will utilise a wide variety of structural biology (X-ray, NMR), biophysics and kinetics approaches, coupled with computational input from collaborating groups. We will focus firstly on ribonuclease H, an archetypal phosphodiester transferase that is also a potent antiviral target, and then expand the programme to FEN1, an important therapeutic target that is well-studied in our laboratories [4].