Exploring the therapeutic potential of chimeric proteins

该项目旨在按照一种新的概念方法设计和进化具有治疗潜力的蛋白水解酶，在该方法中，不同的结合区域和催化区域共价结合在嵌合的“俘获酶”中。这将克服在一个活性部位同时设计结合和催化功能的困难，而不是依赖于模块化设计原则。这项工作的起点一方面是现有的抗体(提供结合)，另一方面是具有混杂活性的蛋白酶的催化潜力(见组合筛选识别导致抑制治疗靶标IL-13的新的混杂基质金属蛋白酶活性；C.Urbach，等人)。L；化学与生物学(2015)，22(11)：1442-52)。稍后，这些结构将被进化(见ChemBioChem.doi：10.1002/cbi.201500295-并在微流控液滴中使用超高通量筛选-见《自然通讯》2015年，6：10008-doi：10.1038/nComms10008)，对其进行机械表征和改进，然后在医学相关靶标上进行测试(与MedImmune的合作者)。

This projects aims to design and evolve proteases with therapeutic potential following a new conceptual approach, in which separate binding and catalytic domains are covalenty combined in chimeric 'captivases'. This will overcome the difficulty of engineering both binding and catalytic functions in one active site, instead relying on modular design principles. Starting points for this effort are one one hand existing antibodies (to provide binding) and on the other the catalytic potential of proteases with promiscuous activities (see 'Combinatorial Screening Identifies Novel Promiscuous Matrix Metalloproteinase Activities That Lead to Inhibition of the Therapeutic Target IL-13; C. Urbach, et al. & F Hollfelder, and L Jermutus; Chemistry & Biology (2015), 22(11):1442-52). Later such constructs will be evolved (see ChemBioChem.doi: 10.1002/cbic.201500295 - and using ultrahigh-throughput screening in microfluidic droplets - see Nature Communications 2015, 6:10008- DOI: 10.1038/ncomms10008), mechanistically characterised and improved and then tested on medically relevant targets (with collaborators at MedImmune).