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Structure-Guided Development of ClpP Agonists with Potent Therapeutic Activities against Staphylococcus aureus Infection

文献类型：期刊论文

作者Zhang, Tao6; Wu, Wei3,6; Zhao, Yanling5; Ding, Ziang5; Wei, Bingyan4; Yang, Teng4; Li, Jiahui3,6; Wang, Pengyu4; Lan, Lefu3,4; Gan, Jianhua1
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-01-06
卷号68期号:2页码:1810-1823
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c02562
英文摘要Peritonitis caused by Staphylococcus aureus poses a severe threat to patients with end-stage renal failure. Treating multidrug-resistant S. aureus infections requires the use of antibiotics with diverse mechanisms of action. Caseinolytic protease P (ClpP) is a promising antibacterial target; however, selective activation of S. aureus ClpP (SaClpP) over human ClpP (HsClpP) remains challenging. We previously identified ( R )-ZG197 as a selective SaClpP agonist, but its potency was suboptimal. Herein, we develop ( R )-ZG197 analogs through a structure-guided approach and examine their structure-activity relationships. Notably, ZY39 demonstrates improved activation of SaClpP and superior binding affinity. Interestingly, while ZY39 facilitates the enzymatic hydrolysis of SaClpP and HsClpP in vitro, it does not target HsClpP in cellular environments. Furthermore, ZY39 effectively inhibits the growth of multidrug-resistant S. aureus strains and shows excellent therapeutic efficacy in a murine model of peritonitis. These findings highlight ZY39 as a promising SaClpP agonist for combating staphylococcal infections.
WOS关键词SMALL-MOLECULE ACTIVATORS ; PERITONEAL-DIALYSIS ; PROTEASE ; ACYLDEPSIPEPTIDES ; DYSREGULATION ; FTSZ
资助项目National Natural Science Foundation of China[22037007] ; National Natural Science Foundation of China[22107109] ; National Natural Science Foundation of China[22307029] ; National Natural Science Foundation of China[2022YFC2804100] ; National Key Research and Development Program of China[2023297] ; Youth Innovation Promotion Association of CAS[GZB20230798] ; Youth Innovation Promotion Association of CAS[XJ009] ; Youth Innovation Promotion Association of CAS[XJ025] ; Youth Innovation Promotion Association of CAS[XJ049] ; Youth Innovation Promotion Association of CAS[XJ051] ; Youth Innovation Promotion Association of CAS[XJ052] ; Postdoctoral Fellowship Program of CPSF ; Institutional Center for Shared Technologies and Facilities of Shanghai Institute of Immunity and Infection, CAS
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001390586400001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/315558]  
专题新药研究国家重点实验室
通讯作者Yang, Cai-Guang
作者单位1.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Chem Biol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Tao,Wu, Wei,Zhao, Yanling,et al. Structure-Guided Development of ClpP Agonists with Potent Therapeutic Activities against Staphylococcus aureus Infection[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(2):1810-1823.
APA Zhang, Tao.,Wu, Wei.,Zhao, Yanling.,Ding, Ziang.,Wei, Bingyan.,...&Yang, Cai-Guang.(2025).Structure-Guided Development of ClpP Agonists with Potent Therapeutic Activities against Staphylococcus aureus Infection.JOURNAL OF MEDICINAL CHEMISTRY,68(2),1810-1823.
MLA Zhang, Tao,et al."Structure-Guided Development of ClpP Agonists with Potent Therapeutic Activities against Staphylococcus aureus Infection".JOURNAL OF MEDICINAL CHEMISTRY 68.2(2025):1810-1823.

入库方式： OAI收割

来源：上海药物研究所

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