KN3014, a piperidine-containing small compound, inhibits auto-secretion of IL-1β from PBMCs in a patient with Muckle–Wells syndrome
| Autor: | Kiyoshi Migita, Takeshi Urano, Naoe Kaneko, Hiroyuki Takeda, Akihiro Yachie, Kazunaga Agematsu, Tomohiro Koga, Koh-ichiro Yoshiura, Tomonari Shigemura, Toshihiro Yamamoto, Takashi Yamazaki, Mie Kurata, Tatsuya Sawasaki, Junya Masumoto, Atsushi Kawakami |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Inflammasomes Interleukin-1beta Anti-Inflammatory Agents lcsh:Medicine Pyrin domain Peripheral blood mononuclear cell Article 03 medical and health sciences Mice 0302 clinical medicine Piperidines NLR Family Pyrin Domain-Containing 3 Protein medicine Autoinflammatory syndrome Animals Humans Secretion Luciferase lcsh:Science Multidisciplinary integumentary system Chemistry lcsh:R Pattern recognition receptor Signal transducing adaptor protein Interleukin Inflammasome Molecular biology Cryopyrin-Associated Periodic Syndromes High-Throughput Screening Assays 030104 developmental biology Drug screening Case-Control Studies Leukocytes Mononuclear lcsh:Q 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) |
| ISSN: | 2045-2322 |
| Popis: | NLRP3, an intracellular pattern recognition receptor, recognizes numerous pathogens and/or its own damage-associated molecules, and forms complexes with the adaptor protein ASC. These complexes constitute the NLRP3 inflammasome, a platform for processing interleukin (IL)-1β and/or IL-18. Several NLRP3 mutations result in constitutive activation of the NLRP3 inflammasome, causing cryopyrin-associated periodic syndrome (CAPS). To the best of our knowledge, small compounds that specifically inhibit inflammasome activation through the pyrin domain (PYD) have not yet been developed. This study describes an attempt to develop small compounds targeting the NLRP3 inflammasome. A core chemical library of 9,600 chemicals was screened against reconstituted NLRP3 inflammasome in a cell-free system with an amplified luminescence proximity homogeneous assay and a cell-based assay by human peripheral blood mononuclear cells (PBMCs). Inflammasome activation was evaluated by ASC-speck formation in human PBMCs, accompanied by IL-1β secretion and processing, and by using IL-1β-based dual operating luciferase (IDOL) mice. The activity of these compounds was evaluated clinically using PBMCs from a patient with Muckle–Wells syndrome (MWS), a type of CAPS, with an R260W mutation in NLRP3. Screening identified KN3014, a piperidine-containing compound targeting the interaction between NLRP3 and ASC through the PYD. KN3014 reduced ASC-speck formation in human PBMCs, luminescence from IDOL mice, and auto-secretion of IL-1β by PBMCs from the patient with MWS. These findings suggest that KN3014 may be an attractive candidate for treatment of MWS, as well as other NLRP3 inflammasomopathies. |
| Databáze: | OpenAIRE |
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