Targeted Degradation of ZBP1 with Covalent PROTACs for Anti‐Inflammatory Treatment of Infections

Angewandte Chemie International Edition, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Z-DNA binding protein 1 (ZBP1) has emerged as a critical pathogen-sensing that upon activation, triggers necroptotic signaling cascades, leading to 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 covalent recognition-based PROTAC (C-PROTAC) molecule ZBP1. It consists DNA aptamer recognition moiety an E3 enzyme-recruiting unit, connected by linker containing N-acyl-N-alkyl sulfonamides (NASA) groups. The binds ZBP1, while NASA-containing facilitates formation bond between target protein. ligase-recruiting unit then directs ubiquitin-proteasome system degrade ZBP1-PROTAC complex. This approach combines high specificity aptamers with efficiency degradation-inducing capabilities PROTACs, providing powerful tool targeted degradation. successful application technology highlights its potential selective elimination disease-associated proteins development novel therapeutic strategies.

Language: Английский

Targeted Degradation of ZBP1 with Covalent PROTACs for Anti‐Inflammatory Treatment of Infections

Angewandte Chemie, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Abstract Z‐DNA binding protein 1 (ZBP1) has emerged as a critical pathogen‐sensing that upon activation, triggers necroptotic signaling cascades, leading to 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 covalent recognition‐based PROTAC (C‐PROTAC) molecule ZBP1. It consists DNA aptamer recognition moiety an E3 enzyme‐recruiting unit, connected by linker containing N ‐acyl‐ ‐alkyl sulfonamides (NASA) groups. The binds ZBP1, while NASA‐containing facilitates formation bond between target protein. ligase‐recruiting unit then directs ubiquitin‐proteasome system degrade ZBP1‐PROTAC complex. This approach combines high specificity aptamers with efficiency degradation‐inducing capabilities PROTACs, providing powerful tool targeted degradation. successful application technology highlights its potential selective elimination disease‐associated proteins development novel therapeutic strategies.

Language: Английский

Site-selective modification of native proteins

Trends in Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский