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Identification of NLRP3 as a covalent target of 1,6-O,O-diacetylbritannilactone against neuroinflammation by quantitative thiol reactivity profiling (QTRP).
Wang, Min-Ran; Huang, Lan-Fang; Guo, Cong; Yang, Jing; Dong, Shuai; Tang, Jiang-Jiang; Gao, Jin-Ming.
Afiliación
  • Wang MR; Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing,
  • Huang LF; Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China.
  • Guo C; Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China.
  • Yang J; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing, Beijing Institute of Lifeomics, Beijing, China.
  • Dong S; Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, Hainan, China.
  • Tang JJ; Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China. Electronic address: tangjiang11@nwsuaf.edu.cn.
  • Gao JM; Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China. Electronic address: dongshuai_1024@163.com.
Bioorg Chem ; 119: 105536, 2022 02.
Article en En | MEDLINE | ID: mdl-34894577
Neuroinflammation plays a key etiological role in the progressive neuronal damage of neurodegenerative diseases. Our phenotypic-based screening discovered 1,6-O,O-diacetylbritannilactone (OABL, 1) from Inula britannica exhibited the potential anti-neuroinflammatory activity as well as a favorable blood-brain barrier penetration. 1 and its active derivative Br-OABL (2) with insert of Br at the C-14 position both modulated TLR4/NF-kB/MAPK pathways. However, proteome-wide identification of 1 binding proteins remains unclear. Here, we employed an adapted isoTOP-ABPP, quantitative thiol reactivity profiling (QTRP) approach, to identify and quantify thiol reactivity binding proteins in murine microglia BV-2 cells. We screened out 15 proteins co-targeted by 1 and 2, which are involved in cellular response to oxidative stress and negative regulation NF-κB transcription factor in biological processes. In site-specific profiling, NLRP3 was identified as a covalent target of 1 and 2 for the first time, and the Cys483 of NLRP3 NACHT domain was identified as one active-site of NLRP3 cysteine residues that can be covalently modified by the α-methylene-γ-lactone moiety. Furthermore, NLRP3 was validated to be directly binded by 1 and 2 by cellular thermo shift assay (CETSA) and activity-based protein profiling (ABPP), and NLRP3 functions were also verified by small interfering RNA approach. Notably, OABL treatment (i.p., 20 mg/kg/day) for 21 days reduced inflammation in 5XFAD mice brain. Together, we applied the QTRP to uncover the binding proteins of OABL in BV-2 cells, among which NLRP3 was revealed as a new covalent target of 1 and 2 against neuroinflammation.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Sesquiterpenos / Proteína con Dominio Pirina 3 de la Familia NLR / Inflamación / Lactonas Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Bioorg Chem Año: 2022 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Sesquiterpenos / Proteína con Dominio Pirina 3 de la Familia NLR / Inflamación / Lactonas Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Bioorg Chem Año: 2022 Tipo del documento: Article