SILAC-based chemoproteomics reveals a neoligan analogue as an anti-inflammatory agent targeting IRGM to ameliorate cytokine storm.
Eur J Med Chem
; 241: 114659, 2022 Nov 05.
Article
in English
| MEDLINE | ID: covidwho-2035972
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 byâvarious patternârecognitionâreceptors (PRRs),âwhichâleadâtoâtheâimmuneâresponse. 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.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Sepsis
/
GTP-Binding Proteins
/
Cytokine Release Syndrome
/
Anti-Inflammatory Agents
Limits:
Animals
/
Humans
Language:
English
Journal:
Eur J Med Chem
Year:
2022
Document Type:
Article
Affiliation country:
J.ejmech.2022.114659
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