Novel strategy for medicinal chemistry utilizing protein knockdown

我们开发了一种方法，通过由与靶蛋白配体连接的cIAP 1配体组成的小分子诱导靶蛋白的选择性降解（蛋白质敲除）。本研究将蛋白质敲低技术应用于生物活性小分子的靶点识别，以及对可能导致神经退行性疾病的错误折叠蛋白质的降解。作为概念证明，使用由cIAP 1配体和与蛋白质结合的小分子组成的连接分子，通过蛋白质组分析鉴定已知的靶蛋白。另一方面，设计并合成了由与cIAP 1配体连接的错误折叠蛋白质结合的染料组成的分子。该分子被证明可以结合多聚谷氨酰胺（polyQ）肽，这是错误折叠蛋白质的主要成分，并减少活细胞中用抗polyQ抗体免疫染色的蛋白质。

We have developed a method that induces selective degradation of target proteins by small molecules consisting of cIAP1 ligand linked to a ligand of the target protein (protein knockdown). In this study, protein knockdown was applied to target identification of bioactive small molecules, and degradation of misfolded proteins which would cause neurodegenerative disorders. As a proof of concept, a known target protein was identified with a proteome analysis using a linked molecule consisting of cIAP1 ligand and a small molecule which binds to a protein. On the other hand, molecules consisting of dyes bound to the misfolded proteins linked to cIAP1 ligand were designed and synthesized. The molecule was proved to bind a poly glutamine (polyQ) peptide, a major component of misfoled proteins, and decrease proteins which were immunostained with anti-polyQ antibody in living cells.