| Autor: |
Moasses Ghafary S; Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 14117-13116, Iran., Soriano-Teruel PM; Centro de Investigación Príncipe Felipe, Targeted Therapies on Cancer and Inflammation Laboratory, 46012 Valencia, Spain.; Centro de Investigación Príncipe Felipe, Polymer Therapeutics Laboratory, 46012 Valencia, Spain., Lotfollahzadeh S; Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 14117-13116, Iran., Sancho M; Centro de Investigación Príncipe Felipe, Targeted Therapies on Cancer and Inflammation Laboratory, 46012 Valencia, Spain., Serrano-Candelas E; ProtoQSAR SL, Centro Europeo de Empresas Innovadoras, Parque Tecnológico de Valencia, 46980 Paterna, Spain., Karami F; Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 14117-13116, Iran., Barigye SJ; ProtoQSAR SL, Centro Europeo de Empresas Innovadoras, Parque Tecnológico de Valencia, 46980 Paterna, Spain.; MolDrug AI Systems SL, 46018 Valencia, Spain., Fernández-Pérez I; Centro de Investigación Príncipe Felipe, Targeted Therapies on Cancer and Inflammation Laboratory, 46012 Valencia, Spain., Gozalbes R; ProtoQSAR SL, Centro Europeo de Empresas Innovadoras, Parque Tecnológico de Valencia, 46980 Paterna, Spain.; MolDrug AI Systems SL, 46018 Valencia, Spain., Nikkhah M; Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 14117-13116, Iran., Orzáez M; Centro de Investigación Príncipe Felipe, Targeted Therapies on Cancer and Inflammation Laboratory, 46012 Valencia, Spain., Hosseinkhani S; Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 14117-13116, Iran. |
| Abstrakt: |
Inflammasomes are multiprotein complexes that represent critical elements of the inflammatory response. The dysregulation of the best-characterized complex, the NLRP3 inflammasome, has been linked to the pathogenesis of diseases such as multiple sclerosis, type 2 diabetes mellitus, Alzheimer's disease, and cancer. While there exist molecular inhibitors specific for the various components of inflammasome complexes, no currently reported inhibitors specifically target NLRP3 PYD homo-oligomerization. In the present study, we describe the identification of QM380 and QM381 as NLRP3 PYD homo-oligomerization inhibitors after screening small molecules from the MyriaScreen library using a split-luciferase complementation assay. Our results demonstrate that these NLRP3 PYD inhibitors interfere with ASC speck formation, inhibit pro-inflammatory cytokine IL1-β release, and decrease pyroptotic cell death. We employed spectroscopic techniques and computational docking analyses with QM380 and QM381 and the PYD domain to confirm the experimental results and predict possible mechanisms underlying the inhibition of NLRP3 PYD homo-interactions. |
