Structure-guided development of selective caseinolytic protease P agonists as antistaphylococcal agents
文献类型：期刊论文
| 作者 | Zhang, Tao7; Wang, Pengyu6; Zhou, Hailing5,7; Wei, Bingyan6; Zhao, Yanling4; Li, Jiahui7; Zhang, Min3; Wu, Wenjuan3; Lan, Lefu5,6; Gan, Jianhua2 |
| 刊名 | CELL REPORTS MEDICINE
 |
| 出版日期 | 2024-12-17 |
| 卷号 | 5期号:12页码:20 |
| ISSN号 | 2666-3791 |
| DOI | 10.1016/j.xcrm.2024.101837 |
| 英文摘要 | Methicillin-resistant Staphylococcus aureus is a ubiquitous pathogen, posing a serious threat to human health worldwide. Thus, there is a high demand for antibiotics with distinct targets. Caseinolytic protease P (ClpP) is a promising target for combating staphylococcal infections; however, selectively activating S. aureus ClpP (SaClpP) rather than Homo sapiens ClpP (HsClpP) remains challenging. Herein, we rationally design and identify ZG297 by structure-based strategy. It binds and activates SaClpP instead of HsClpP. This is due to differentiated ligand binding attributed to crossed "tyrosine/histidine"amino acid pairs. ZG297 substantially inhibits the growth of a broad panel of S. aureus strains in vitro, outperforming the selective (R)ZG197 agonist. ZG297 also functions as a potent antibiotic against multidrug-resistant S. aureus infections in Galleria mellonella larvae, zebrafish, murine skin, and thigh infection models. Collectively, we demonstrate that ZG297 is a safer and more potent antistaphylococcal agent than acyldepsipeptide 4 and (R)-ZG197. |
| WOS关键词 | SMALL-MOLECULE ACTIVATORS ; CLPP PROTEASE ; FTSZ ; DYSREGULATION ; INHIBITORS ; DISCOVERY ; VIRULENCE ; EFFICACY ; INSIGHTS ; MODEL |
| 资助项目 | National Key Research and Devel-opment Program of China[2022YFC2804100] ; National Natural Sci-ence Foundation of China[22037007] ; National Natural Sci-ence Foundation of China[22107109] ; National Natural Sci-ence Foundation of China[22307029] ; National Natural Sci-ence Foundation of China[81971990] ; Youth Innovation Promotion Association of CAS[2023297] ; Postdoctoral Fellowship Program of CPSF[GZB20230798] |
| WOS研究方向 | Cell Biology ; Research & Experimental Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:001390843800001 |
| 出版者 | CELL PRESS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/315564]  |
| 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.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China 2.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China 3.Tongji Univ, Sch Med, Shanghai East Hosp, Dept Lab Med, Shanghai 200123, Peoples R China 4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 7.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,Wang, Pengyu,Zhou, Hailing,et al. Structure-guided development of selective caseinolytic protease P agonists as antistaphylococcal agents[J]. CELL REPORTS MEDICINE,2024,5(12):20. |
| APA | Zhang, Tao.,Wang, Pengyu.,Zhou, Hailing.,Wei, Bingyan.,Zhao, Yanling.,...&Yang, Cai-Guang.(2024).Structure-guided development of selective caseinolytic protease P agonists as antistaphylococcal agents.CELL REPORTS MEDICINE,5(12),20. |
| MLA | Zhang, Tao,et al."Structure-guided development of selective caseinolytic protease P agonists as antistaphylococcal agents".CELL REPORTS MEDICINE 5.12(2024):20. |
入库方式： OAI收割
来源：上海药物研究所
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