Identification of Azalamellarin N as a Pyroptosis Inhibitor

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  • Takouda Jun
    Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University
  • Nakamura Moeka
    Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University
  • Murasaki Akane
    Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University
  • Shimosako Waka
    Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University
  • Hidaka Aoi
    Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University
  • Honda Shino
    Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University
  • Tanimura Susumu
    Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University
  • Ishibashi Fumito
    Division of Marine Life Science and Biochemistry, Graduate School of Fisheries and Environmental Sciences, Nagasaki University
  • Kawasaki Norihiko
    Department of Pharmaceutical Organic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University
  • Ishihara Jun
    Department of Pharmaceutical Organic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University
  • Fukuda Tsutomu
    Environmental Protection Center, Nagasaki University Graduate School of Engineering, Nagasaki University
  • Takeda Kohsuke
    Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University

説明

<p>Pyroptosis is a form of regulated cell death that promotes inflammation; it attracts much attention because its dysregulation leads to various inflammatory diseases. To help explore the precise mechanisms by which pyroptosis is regulated, in this study, we searched for chemical compounds that inhibit pyroptosis. From our original compound library, we identified azalamellarin N (AZL-N), a hexacyclic pyrrole alkaloid, as an inhibitor of pyroptosis induced by R837 (also called imiquimod), which is an agonist of the intracellular multiprotein complex nucleotide-binding and oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. However, whereas the effect of AZL-N on R837-induced pyroptosis was relatively weak, AZL-N strongly inhibited pyroptosis induced by extracellular ATP or nigericin, which are different types of NLRP3 inflammasome agonists. This was in contrast with the results that MCC950, a well-established NLRP3 inhibitor, consistently inhibited pyroptosis irrespective of the type of stimulus. We also found that AZL-N inhibited activation of caspase-1 and apoptosis-associated speck-like proteins containing a caspase activation and recruitment domain (ASC), which are components of the NLRP3 inflammasome. Analysis of the structure–activity relationship revealed that a lactam ring of AZL-N, which has been shown to contribute to the strong binding of AZL-N to its known target protein kinases, is required for its inhibitory effects on pyroptosis. These results suggest that AZL-N inhibits pyroptosis by targeting molecule(s), which may be protein kinase(s), that act upstream of NLRP3 inflammasome activation, rather than by directly targeting the components of the NLRP3 inflammasome. Further identification and analysis of target molecule(s) of AZL-N will shed light on the regulatory mechanisms of pyroptosis, particularly those depending on proinflammatory stimuli.</p>

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