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.