Identification of NLRP3(PYD) Homo-Oligomerization Inhibitors with Anti-Inflammatory Activity
Por:
S. GHAFARY, P. SORIANO-TERUEL, S. LOTFOLLAHZADEH, M. SANCHO, E. SERRANO-CANDELAS, F. KARAMI, S. BARIGYE, I. FERNANDEZ-PEREZ, R. GOZALBES, M. NIKKHAH, M. ORZAEZ and S. HOSSEINKHANI
Publicada:
1 feb 2022
Resumen:
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-beta 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.
Filiaciones:
S. GHAFARY:
Tarbiat Modares Univ, Fac Biol Sci, Dept Nanobiotechnol, Tehran 1411713116, Iran
:
Ctr Investigac Principe Felipe, Targeted Therapies Canc & Inflammat Lab, Valencia 46012, Spain
Ctr Investigac Principe Felipe, Polymer Therapeut Lab, Valencia 46012, Spain
S. LOTFOLLAHZADEH:
Tarbiat Modares Univ, Fac Biol Sci, Dept Nanobiotechnol, Tehran 1411713116, Iran
:
Ctr Investigac Principe Felipe, Targeted Therapies Canc & Inflammat Lab, Valencia 46012, Spain
E. SERRANO-CANDELAS:
ProtoQSAR SL, Ctr Europeo Empresas Innovadoras, Parque Tecnol Valencia, Paterna 46980, Spain
F. KARAMI:
Tarbiat Modares Univ, Fac Biol Sci, Dept Nanobiotechnol, Tehran 1411713116, Iran
S. BARIGYE:
ProtoQSAR SL, Ctr Europeo Empresas Innovadoras, Parque Tecnol Valencia, Paterna 46980, Spain
MolDrug Syst SL, Valencia 46018, Spain
I. FERNANDEZ-PEREZ:
Ctr Investigac Principe Felipe, Targeted Therapies Canc & Inflammat Lab, Valencia 46012, Spain
R. GOZALBES:
ProtoQSAR SL, Ctr Europeo Empresas Innovadoras, Parque Tecnol Valencia, Paterna 46980, Spain
MolDrug Syst SL, Valencia 46018, Spain
M. NIKKHAH:
Tarbiat Modares Univ, Fac Biol Sci, Dept Nanobiotechnol, Tehran 1411713116, Iran
:
Ctr Investigac Principe Felipe, Targeted Therapies Canc & Inflammat Lab, Valencia 46012, Spain
S. HOSSEINKHANI:
Tarbiat Modares Univ, Fac Biol Sci, Dept Biochem, Tehran 1411713116, Iran
Green Published, gold
|