Directing protein modification in living systems with bifunctional molecules

蛋白质翻译后修饰（PTMs）是蛋白质在细胞中产生后结构的化学变化，通常由酶引入和/或去除。在人类蛋白质组中，有超过1000类的PTM被引入到超过100万个不同的蛋白质位点上。ptm通常对蛋白质功能有深远的影响，调节生物学的各个方面，并为每一种疾病的干预提供了基础或机会。最近，出现了一种新的药物发现范式，即双功能分子诱导复合物组装，催化ptm从头开始，最突出的是诱导泛素化和靶蛋白的降解（所谓的“PROTACs”），这种模式最近进入临床试验。由于这些药物可以选择细胞中已经存在的酶催化功能，因此它们可以在低占用率和与蛋白质功能无关的位点上传递强大的生物效应，从而推翻了以前关于小分子可以实现的假设。利用泰特集团在化学工具设计方面的深厚专业知识，了解和利用生命系统中的ptm，沃尔波特实验室强大的肽选择平台，以及默沙东在药物发现和开发方面的世界领先能力，您将设计，合成和开发一类新的双功能分子，能够诱导蛋白质功能和定位的巨大变化，具有操纵生物学和调节疾病结果的巨大潜力。

Protein post-translational modifications (PTMs) are chemical changes to the structure of a protein after it has been made in the cell and are typically introduced and/or removed by enzymes. There are over 1000 classes of PTM in the human proteome introduced at over 1 million distinct sites on proteins. PTMs often have a profound effect on protein function and regulate all aspects of biology and underlie or represent opportunities for intervention in every type of disease. Recently, a new drug discovery paradigm has emerged whereby bifunctional molecules induce assembly of complexes which catalyse PTMs de novo, most prominently to induce ubiquitination and degradation of a target protein (so-called 'PROTACs'), a modality recently progressed into clinical trials. Since they co-opt enzyme catalytic functions already present in cells, such drugs can deliver potent biological effects at low occupancy and at sites unrelated to protein function, overturning previous assumptions about what can be achieved with small molecules. Drawing on the deep expertise of the Tate group in the design of chemical tools to understand and exploit PTMs in living systems, a powerful peptide selection platform in the Walport lab, and the world-leading capabilities at MSD in drug discovery and development, you will design, synthesize and develop a new class of bifunctional molecules capable of inducing dramatic changes in protein function and localisation, with profound potential for manipulating biology and modulating disease outcomes.