Discovery and Engineering of New Enzymes for Late Stage Functionalisation

该项目旨在发现和设计能够影响复杂分子的区域选择性多样化的新型酶（生物催化剂），从而更有效和环境可持续地生产对抗疾病迫切需要的药物。例如，许多领先的药物（重磅药物）都含有卤素取代基。然而，传统的化学卤化方法用于引入卤素缺乏选择性，使用有毒试剂和有害溶剂，成本高昂。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，利用更良性的试剂和可再生原料，提供关键的卤化药品和其他中间体。通过与Prozomix Ltd的合作，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酶的基因组和宏基因组；建立这些酶的高通量克隆、表达和筛选方法；（iii）进一步设计和扩大所选酶的底物范围，增加药物支架的大小和复杂性，使其能够在后期进行有效的区域选择性多样化。

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.