Dr. Rentang Huang, Dr. Yusi Hu, Yi-Fan Wang, Shiyu Zhang, Dr. Prof. Zhi-Gang Wang, Dr. Prof. Dai-Wen Pang, Dr. Prof. Shu-Lin Liu
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引用次数: 0
摘要
Z-DNA结合蛋白1 (ZBP1)是一种关键的病原体感应蛋白,一旦激活,就会触发坏死信号级联反应,导致强烈的炎症反应,并可能导致严重的组织损伤。然而,目前还缺乏专门开发的有效抑制或降解ZBP1的药物。在这项研究中,我们开发了一个有效的基于共价识别的PROTAC (C-PROTAC)分子来降解ZBP1。它由一个DNA适体作为识别片段和一个E3酶招募单元组成,由一个含有n -酰基- n -烷基磺酰胺(NASA)基团的连接体连接。DNA适体特异性结合ZBP1,而含有nasa的连接子促进PROTAC和靶蛋白之间形成共价键。E3酶招募单元然后指导泛素-蛋白酶体系统降解ZBP1-PROTAC复合物。该方法结合了DNA适体的高特异性、共价结合的效率和PROTACs的降解诱导能力,为靶向蛋白降解提供了强有力的工具。这项技术在ZBP1上的成功应用凸显了它在选择性消除疾病相关蛋白和开发新的治疗策略方面的潜力。
Targeted Degradation of ZBP1 with Covalent PROTACs for Anti-Inflammatory Treatment of Infections
Z-DNA binding protein 1 (ZBP1) has emerged as a critical pathogen-sensing protein that upon activation, triggers necroptotic signaling cascades, leading to a potent inflammatory response and potentially causing significant tissue damage. However, available drugs specifically developed for the effective inhibition or degradation of ZBP1 is still lacking so far. In this study, we developed a potent covalent recognition-based PROTAC (C-PROTAC) molecule for the degradation of ZBP1. It consists of a DNA aptamer as the recognition moiety and an E3 enzyme-recruiting unit, connected by a linker containing N-acyl-N-alkyl sulfonamides (NASA) groups. The DNA aptamer specifically binds to ZBP1, while the NASA-containing linker facilitates the formation of a covalent bond between the PROTAC and the target protein. The E3 ligase-recruiting unit then directs the ubiquitin-proteasome system to degrade the ZBP1-PROTAC complex. This approach combines the high specificity of DNA aptamers with the efficiency of covalent binding and the degradation-inducing capabilities of PROTACs, providing a powerful tool for targeted protein degradation. The successful application of this technology to ZBP1 highlights its potential for the selective elimination of disease-associated proteins and the development of novel therapeutic strategies.
期刊介绍:
Angewandte Chemie, a journal of the German Chemical Society (GDCh), maintains a leading position among scholarly journals in general chemistry with an impressive Impact Factor of 16.6 (2022 Journal Citation Reports, Clarivate, 2023). Published weekly in a reader-friendly format, it features new articles almost every day. Established in 1887, Angewandte Chemie is a prominent chemistry journal, offering a dynamic blend of Review-type articles, Highlights, Communications, and Research Articles on a weekly basis, making it unique in the field.