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Discovery of GPR84 Fluorogenic Probes Based on a Novel Antagonist for GPR84 Bioimaging

文献类型：期刊论文

作者Xiao, Yufeng4,5; Chen, Jing4,5; Li, Shaoxian4,5; Zhang, Qing1,3,4,5; Liu, Yin2; Chen, Linhai1,4,5; Sun, Yadi3,4,5; Gu, Min5; Xie, Xin1,2,3,4,5; Nan, Fajun1,3,4,5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-07-01
页码16
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00359
通讯作者Xie, Xin(xxie@simm.ac.cn) ; Nan, Fajun(fjnan@simm.ac.cn)
英文摘要GPR84 is a promising therapeutic target and biomarker for a range of diseases. In this study, we reported the discovery of BINOL phosphate (BINOP) derivatives as GPR84 antagonists. By investigating the structure-activity relationship, we identified 15S as a novel GPR84 antagonist. 15S exhibits low nanomolar potency and high selectivity for GPR84, while its enantiomer 15R is less active. Next, we rationally designed and synthesized a series of GPR84 fluorogenic probes by conjugating Nile red and compound 15S. The leading hybrid, probe F8, not only retained GPR84 activity but also exhibited low nonspecific binding and a turn-on fluorescent signal in an apolar environment. F8 enabled visualization and detection of GPR84 in GPR84-overexpressing HEK293 cells and lipopolysaccharide-stimulated neutrophils. Furthermore, we demonstrated that F8 can detect upregulated GPR84 protein levels in mice models of inflammatory bowel disease and acute lung injury. Thus, compound F8 represents a promising tool for studying GPR84 functions.
WOS关键词PROTEIN-COUPLED-RECEPTOR ; FLUORESCENT-PROBES ; LIPID ORDER ; EXPRESSION ; LIGANDS
资助项目National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82330113] ; Youth Innovation Promotion Association of CAS[2020283]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001261346300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/312152]  
专题新药研究国家重点实验室
通讯作者Xie, Xin; Nan, Fajun
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Xiao, Yufeng,Chen, Jing,Li, Shaoxian,et al. Discovery of GPR84 Fluorogenic Probes Based on a Novel Antagonist for GPR84 Bioimaging[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024:16.
APA Xiao, Yufeng.,Chen, Jing.,Li, Shaoxian.,Zhang, Qing.,Liu, Yin.,...&Nan, Fajun.(2024).Discovery of GPR84 Fluorogenic Probes Based on a Novel Antagonist for GPR84 Bioimaging.JOURNAL OF MEDICINAL CHEMISTRY,16.
MLA Xiao, Yufeng,et al."Discovery of GPR84 Fluorogenic Probes Based on a Novel Antagonist for GPR84 Bioimaging".JOURNAL OF MEDICINAL CHEMISTRY (2024):16.

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来源：上海药物研究所

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