Single-domain antibody, proteolysis-targeting chimera constructs (sdAb-PROTAC) for the specific intra-cellular degradation of protein targets

癌症中许多调节失调的蛋白质，即过度表达和/或突变的蛋白质，可以被归类为不可用药，这意味着它们没有酶功能或任何明显易于结合的结合部位来设计小分子抑制剂。蛋白水解靶向嵌合体分子(PROTAC)是一种双功能分子，它能诱导蛋白质靶标与E3连接酶之间的亲和，从而启动蛋白质靶标的多泛素化，导致蛋白酶体的降级。该项目的目的是利用单域抗体(SdAbs)的选择性和稳定性来生产PROTAC结合物，该结合物能够使以前无法下药的靶标在细胞内蛋白质脱脂。

Many dysregulated proteins in cancers, ones which are over-expressed and/ or mutated, can be classified as 'undruggable', meaning they do not have enzymatic function or any obviously amenable binding site to design a small-molecule inhibitor for. Proteolysis-targeting chimera molecules (PROTACs) are bifunctional molecules that induce proximity between a protein target and an E3 ligase, which initiates polyubiquitination of the protein target leading to proteosomal degredation. The aim of this project is to utilise the selectivity and stability of single-domain antibodies (sdAbs) to produce PROTAC conjugates capable of intracellular protein degredation of previously 'undruggable' targets.