Discovery and Engineering of New Enzymes for Late Stage Functionalisation

该项目旨在发现和设计新的酶（生物催化剂），这些酶可以影响复杂分子的区域选择性多样化，从而能够更有效和环境可持续地生产急需的药物。例如，许多领先的药物（重磅炸弹药物）具有卤素取代基。然而，用于引入卤素的传统化学卤化方法缺乏选择性，并且使用有毒试剂以及有害溶剂，所有这些都具有显著的成本。在这个项目中，我们将开发更可持续的酶促方法，在温和的条件下，在水中，利用更温和的试剂和可再生的原料来提供关键的卤化药品和其他中间体。与Prozomix Ltd合作，我们的目标是：（i）开发新的生物信息学方法，用于挖掘新的卤化酶和其他合成有用的酶的基因组和宏基因组;（ii）建立高通量克隆，表达和筛选这些酶的方法;（iii）进一步设计和扩大所选酶的底物范围，增加了可以进行有效的后期区域选择性多样化的药物支架的尺寸和复杂性。

The project aims to discover and engineer novel enzymes (biocatalysts) that can affect regioselective diversification of complex molecules enabling more efficient and environmentally sustainable production of pharmaceuticals which are urgently required to combat disease. For example, many of the leading pharmaceuticals (blockbuster drugs), possess halogen substituents. However, the traditional chemical halogenation methods that are used to introduce halogens lack selectivity and use toxic reagents as well as deleterious solvents, all of which come at significant cost. In this project we will develop more sustainable enzymatic methods to deliver key halogenated pharmaceutical products and other intermediates under mild conditions, in water, utilising more benign reagents and renewable feedstocks. In collaboration with Prozomix Ltd, we aim to: (i) Develop new bioinformatics approaches for mining genomes and metagenomes for new halogenases and other synthetically useful enzymes; (ii) Establish methods for high throughput cloning, expression and screening of these enzymes; (iii) Further engineer and expand the substrate scope of the selected enzymes, increasing the size and complexity of pharmaceutical scaffolds that can be subjected to efficient late-stage regioselective diversification.