Metal Fluoride-based tools for understanding phosphodiesterases

最近，我们开发了一系列无机氟化金属化合物，作为转移磷酸单酯酶的过渡态类似物（TSAs）。可以说，它们代表了已知生物催化剂中最准确的TSAs[1-3]。我们现在打算探索相关化合物的开发和应用，这些化合物将类似地改变对转移磷酸二酯的酶的催化和抑制的理解。这类酶包括许多具有极高价值的成员。它包含许多在所有生命领域中操纵和维持DNA和RNA的酶，包括丰富的治疗靶点（从抗病毒到抗癌）和支撑分子和合成生物学的酶（从聚合酶到限制性内切酶）。我们将利用各种各样的结构生物学（x射线，核磁共振），生物物理学和动力学方法，再加上来自合作小组的计算输入。我们将首先关注核糖核酸酶H，这是一种典型的磷酸二酯转移酶，也是一种有效的抗病毒靶点，然后将项目扩展到FEN1，这是一个重要的治疗靶点，在我们的实验室中得到了很好的研究。

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].