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SILAC-based chemoproteomics reveals a neoligan analogue as an anti-inflammatory agent targeting IRGM to ameliorate cytokine storm.
- Source :
-
European Journal of Medicinal Chemistry . Nov2022, Vol. 241, pN.PAG-N.PAG. 1p. - Publication Year :
- 2022
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Abstract
- Cytokine storm is a key feature of sepsis and severe stage of COVID-19, and the immunosuppression after excessive immune activation is a substantial hazard to human life. Both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are recognized by various pattern recognition receptors (PRRs), which lead to the immune response. A number of neolignan analogues were synthesized in this work and showed powerful anti-inflammation properties linked to the response to innate and adaptive immunity, as well as NP-7 showed considerable anti-inflammatory activity at 100 nM. On the sepsis model caused by cecum ligation and puncture (CLP) in C57BL/6J mice, NP-7 displayed a strong regulatory influence on cytokine release. Then a photo-affinity probe of NP-7 was synthesized and chemoproteomics based on stable isotope labeling with amino acids in cell cultures (SILAC) identified Immunity-related GTPase M (IRGM) as a target suppressing cytokine storm, which was verified by competitive pull-down, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and molecular dynamics simulations. [Display omitted] • Neolignan analogues showed considerable anti-inflammatory efficacy on inflammatory response to innate and adaptive immune responses. • Treatment with NP-7 on CLP-induced sepsis model demonstrated a significant therapeutic benefit. • Chemoproteomics revealed NP-7 played a role of immunoregulation due to target IRGM. • IRGM may contribute to the development of a novel therapeutic target for sepsis and severe cytokine release. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 241
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 158746970
- Full Text :
- https://doi.org/10.1016/j.ejmech.2022.114659