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基于 SILAC 的化学生物组学揭示了一种新的脂联素类似物作为一种抗炎剂，通过靶向 IRGM 来改善细胞因子风暴。

SILAC-based chemoproteomics reveals a neoligan analogue as an anti-inflammatory agent targeting IRGM to ameliorate cytokine storm.

机构信息

School of Chinese Materia Medica, and State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.

China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457, China.

出版信息

Eur J Med Chem. 2022 Nov 5;241:114659. doi: 10.1016/j.ejmech.2022.114659. Epub 2022 Aug 8.

DOI:10.1016/j.ejmech.2022.114659
PMID:35970074
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9359778/
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.

摘要

细胞因子风暴是脓毒症和 COVID-19 严重阶段的一个关键特征，过度免疫激活后的免疫抑制对人类生命是一个实质性的危险。病原体相关分子模式 (PAMPs) 和损伤相关分子模式 (DAMPs) 都被各种模式识别受体 (PRRs) 识别，从而引发免疫反应。本工作合成了一些新木脂素类似物，表现出与先天和适应性免疫反应相关的强大抗炎特性，并且 NP-7 在 100 nM 时表现出相当大的抗炎活性。在 C57BL/6J 小鼠的盲肠结扎和穿刺 (CLP) 引起的脓毒症模型中，NP-7 对细胞因子释放显示出强烈的调节作用。然后合成了 NP-7 的光亲和探针，并基于稳定同位素标记与细胞培养中的氨基酸 (SILAC) 的化学生物组学鉴定出免疫相关 GTP 酶 M (IRGM) 作为抑制细胞因子风暴的靶标，这通过竞争性下拉、细胞热转移测定 (CETSA)、药物亲和反应靶标稳定性 (DARTS) 和分子动力学模拟得到了验证。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/3740a8fb212b/gr10_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/0feefa2b268c/ga1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/2c51451ff592/sc1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/f55dcdadfd87/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/b343897fbc4d/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/caa281174c97/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/c67ade563d38/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/34c141053534/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/5e15c480c0c1/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/723654c640bd/sc2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/ae2284fe7304/gr7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/3ff05d64f125/gr8_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/553b7b60a734/gr9_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/3740a8fb212b/gr10_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/0feefa2b268c/ga1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/2c51451ff592/sc1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/f55dcdadfd87/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/b343897fbc4d/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/caa281174c97/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/c67ade563d38/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/34c141053534/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/5e15c480c0c1/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/723654c640bd/sc2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/ae2284fe7304/gr7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/3ff05d64f125/gr8_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/553b7b60a734/gr9_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48e3/9359778/3740a8fb212b/gr10_lrg.jpg

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