铜配合物类自噬相关蛋白ATG4B抑制剂的发现及机制研究

ATG4B是调控LC3成熟及去脂化的关键蛋白，在自噬过程中发挥着重要作用。研究表明ATG4B是疾病治疗中的潜在靶点，抑制ATG4B可能成为疾病治疗的新手段。我们实验发现二价铜离子能有效抑制ATG4B的酶切活性，优于文献报道的其他ATG4B小分子抑制剂。但二价铜离子易被螯合，二价铜在体内几乎均以配合物形式存在。因此，铜配合物可能发展成为新型的ATG4B抑制剂。本项目拟在前期ATG4B抑制剂筛选和功能表征（Autophagy，2019）的基础上深入研究。旨在寻找更为高效、专一的铜配合物类ATG4B抑制剂，同时系统阐明铜配合物如何调节LC3去脂化及自噬过程等关键科学问题。本研究为发现新型金属配合物类ATG4B抑制剂，理解ATG4B在自噬通路中的调控机制以及ATG4B在疾病中的作用提供依据，也为以ATG4B为靶点的药物发现提供新思路。

ATG4B is a critical protein in the autophagy process that regulates the priming and delipidation of LC3. Studies have shown that ATG4B could be a promising drug target, and inhibition of ATG4B may serve as a potential therapeutic strategy. We previously found that Cu (II) ions could efficiently inhibit ATG4B activity, which is more potent than other reported ATG4B inhibitors. However, Cu (II) ions are easily chelated and almost all of the Cu (II) exists in the form of complexes in the human body. Therefore, copper complexes may develop into novel ATG4B inhibitors. Based on our previous work on inhibitor screening and functional characterization of ATG4B, we will further find more potent and specific copper complexes as ATG4B inhibitors, and answer the key scientific questions: How does copper complexes affect the activity of ATG4B and the process of autophagy? This study will provide more data for discovering novel metal complexes as ATG4B inhibitors, understanding the key effects of ATG4B in autophagy and diseases, and also offer new insights for ATG4B-based drug discovery.