A5049956627- Inflammasome and immune disorders
- Peptidase Inhibition and Analysis
- Tryptophan and brain disorders
- Sphingolipid Metabolism and Signaling
- Calcium signaling and nucleotide metabolism
- Heme Oxygenase-1 and Carbon Monoxide
- Gout, Hyperuricemia, Uric Acid
- Lung Cancer Research Studies
- Protein Degradation and Inhibitors
- Neonatal Respiratory Health Research
- Ubiquitin and proteasome pathways
- Kawasaki Disease and Coronary Complications
- Cholesterol and Lipid Metabolism
- Receptor Mechanisms and Signaling
- interferon and immune responses
- IL-33, ST2, and ILC Pathways
University of Bonn
2020-2025
The bifunctional compound V2 induced a VHL-dependent NLRP3 degradation. postulated ternary complex formation involves the molecular interaction of (cyan) to binding sites VHL (magenta) and (orange).
Inflammasomes are cytosolic multimeric signaling complexes of the innate immune system that induce activation caspases. The NOD‐like receptor NLRP9 recruits adaptor protein ASC to form an ASC‐dependent inflammasome limit rotaviral replication in intestinal epithelial cells, but only little is known about molecular mechanisms regulating and driving its assembly. Here, we present crystal structure human pyrin domain (PYD). We show PYD not able self‐polymerize nor nucleate specks HEK293T cells....
In recent drug development efforts, particular emphasis has been devoted to the chemical interference with NLRP3 inflammasome. A series of 12 tailored sulfonylureas was designed, prepared through convergent syntheses a final sodium hydride-promoted reaction isocyanates and sulfonamides, subjected systematic, high-performance liquid chromatography-based survey stability, critical issue in terms preparation, storage, application. binding determined by surface plasmon resonance spectroscopy....
This study explores PROTACs for NLRP3, the key player in innate immunity. We utilized a thiophene analogue of NLRP3 inhibitor MCC950 and employed CuAAC chemistry assembly bearing various linkers recruiting three different E3 ligases. Compounds were evaluated bidirectional thermal stability studies with IL-1β release protein abundance assessed cellular assays. PROTAC V2 induces significant VHL-dependent degradation constitutes valuable tool to decipher intricate details inflammasome.
Extracellular signals drive the nucleation of NLRP3 inflammasome which leads to release cytokines and causes inflammatory events. Hence, has gained enormous momentum in biomedical basic research. The detailed mechanisms generation regulation remain be elucidated. Our study was directed toward design, convergent synthesis, initial biochemical evaluation activity-based probes addressing NLRP3. For this purpose, were assembled from a CRID3/MCC950-related NLRP3-binding unit, linker portion...
Abstract NLRP3 is an intracellular sensor protein whose activation by a broad spectrum of exogenous and endogenous stimuli leads to inflammasome formation pyroptosis. The mechanisms leading the way how antagonistic small molecules function remain poorly understood. Here we report cryo-electron microscopy structures full-length in its native form complexed with inhibitor CRID3 (also named MCC950). Inactive, ADP-bound decamer composed homodimers intertwined LRR domains that assemble...
Targeted protein degradation, spearheaded by proteolysis targeting chimeras (PROTACs), has emerged as an auspicious avenue for drug discovery. NLRP3, a key player in innate immunity associated with several inflammatory diseases, not yet been targeted PROTACs. This study explores NLRP3 PROTACs potential therapeutic candidates. We exploited the diaryl sulfonylurea pharmacophore and utilized thiophene analog of inhibitor MCC950 PROTAC assembly. Using CuAAC chemistry, heterobifunctional...
The NLRP3 inflammasome is an intracellular protein complex that causes inflammation via the release of IL-1β and pyroptosis. activation associated with many age-related inflammatory diseases, inhibition a promising therapeutic strategy. We previously performed DNA encoded library screen to identify novel binding molecules. Herein we describe characterization BAL-0028 as potent specific inhibitor signaling. Notably, poor mouse but inhibits human primate nanomolar potency. Using cellular...