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

癌症中的许多失调蛋白，那些过度表达和/或突变的蛋白，可以被归类为“不可药物”，这意味着它们不具有酶功能或任何明显适合的结合位点来设计小分子抑制剂。靶向蛋白水解嵌合体分子（Proteolysis-targeting chimera molecules, PROTACs）是一种双功能分子，可诱导蛋白靶点和E3连接酶之间的接近，从而启动蛋白靶点的多泛素化，导致蛋白体降解。该项目的目的是利用单域抗体（sabs）的选择性和稳定性来生产PROTAC偶联物，这种偶联物能够在细胞内降解以前“不可药物”的靶标。

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.