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

Angewandte Chemie International Edition, Год журнала: 2025, Номер unknown

Опубликована: Март 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.

Язык: Английский

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

Angewandte Chemie, Год журнала: 2025, Номер unknown

Опубликована: Март 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.

Язык: Английский

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O-Cyanobenzaldehydes Irreversibly Modify Both Buried and Exposed Lysine Residues in Live Cells

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Март 27, 2025

Lysine residue represents an attractive site for covalent drug development due to its high abundance (5.6%) and critical functions. However, very few lysines have been characterized be accessible ligands perturb the protein functions, owing their protonation state adjacent steric hindrance. Herein, we report a new lysine bioconjugation chemistry, O-cyanobenzaldehyde (CNBA), that enables selective modification of ε-amine form iso-indolinones under physiological conditions. Activity-based proteome profiling enabled mapping 3451 residues 85 endogenous kinases in live cells, highlighting potential modifying hyper-reactive within or buried catalytic kinome. Further crystallography mass spectrometry confirmed K271_ABL1 K162_AURKA are covalently targetable sites kinases. Leveraging structure-based design, incorporated CNBA into core structure Nutlin-3 irreversibly inhibit MDM2-p53 interaction by targeting exposed K94 on surface murine double minute 2. Importantly, demonstrated application as lysine-recognized agent developing antibody-drug conjugates. The results collectively validate efficient with broad applications both cells.

Язык: Английский

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Advancing Covalent Ligand and Drug Discovery beyond Cysteine

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Май 22, 2025

Targeting intractable proteins remains a key challenge in drug discovery, as these often lack well-defined binding pockets or possess shallow surfaces not readily addressed by traditional design. Covalent chemistry has emerged powerful solution for accessing protein sites difficult to ligand regions. By leveraging activity-based profiling (ABPP) and LC-MS/MS technologies, academic groups industry have identified cysteine-reactive ligands that enable selective targeting of challenging modulate previously inaccessible biological pathways. Cysteines within are rare, however, developing covalent target additional residues hold great promise further expanding the ligandable proteome. This review highlights recent advancements amino acids beyond cysteine with an emphasis on tyrosine- lysine-directed their applications chemical biology therapeutic development. We outline process using proteomic methodology, highlighting successful examples discuss considerations future expansion acid proteins.

Язык: Английский

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Discovery of MK-4688: an Efficient Inhibitor of the HDM2–p53 Protein–Protein Interaction

Journal of Medicinal Chemistry, Год журнала: 2021, Номер 64(21), С. 16213 - 16241

Опубликована: Окт. 29, 2021

Identification of low-dose, low-molecular-weight, drug-like inhibitors protein–protein interactions (PPIs) is a challenging area research. Despite the challenges, therapeutic potential PPI inhibition has driven significant efforts toward this goal. Adding to recent success in area, we describe herein our optimize novel purine carboxylic acid-derived inhibitor HDM2–p53 into series low-projected dose with overall favorable pharmacokinetic and physical properties. Ultimately, strategy focused on leveraging known binding hot spots coupled biostructural information guide design conformationally constrained analogs focus efficiency metrics led discovery MK-4688 (compound 56), highly potent, selective, low-molecular-weight suitable for clinical investigation.

Язык: Английский

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