Understanding interspecies drug response variations between human and rodent P2X7 receptors
文献类型：期刊论文
| 作者 | Guo, Chang-Run8,9,10; Sheng, Danqi7; Li, Ji-Yuan5,6; Li, Tian-Tian9,10; Yao, Jia-Bao9,10; Zhang, Rui5; Huang, Ye9,10; Zhao, Ying-Ying9,10; Wang, Dong-Ping9,10; Chen, Jie9,10 |
| 刊名 | NATURE COMMUNICATIONS
 |
| 出版日期 | 2025-12-01 |
| 卷号 | 16期号:1页码:20 |
| DOI | 10.1038/s41467-025-65847-0 |
| 英文摘要 | Despite intensive development, P2X7 modulators have struggled in translation due to human genetic variability and species-dependent drug responses. Here, we identify PSFL1191, a portal-of-central-pocket (PCP)-site inhibitor selective for human and panda P2X7, but inactive against rodents. Cryo-EM structures revealed two distinct PCP sub-pockets: PCP1, a rigid base pocket demanding precise steric complementarity with PSFL1191, and PCP2, a conserved middle cavity targeted by JNJ-54175446, a clinical candidate unaffected by species differences. Species selectivity maps to a deep PCP1 motif (V312-Y295-M105-F103-P96). In P2rx7A312V/A312V mice, PSFL1191 markedly altered macrophage-mediated bacterial clearance and wound healing while preserving basal physiology, effects absent in wild-type animals. Our findings establish the structural basis for interspecies pharmacological divergence in P2X7 modulation and highlight transgenic models as powerful tools for predicting therapeutic efficacy, thereby enabling more precise and efficient drug discovery. |
| WOS关键词 | P2X(7) RECEPTOR ; RHEUMATOID-ARTHRITIS ; ANTAGONIST ; IDENTIFICATION ; MECHANISM ; EFFICACY ; MOUSE |
| 资助项目 | Innovation and Entrepreneurship (Shuangchuang) Program of Jiangsu Province, JSSCTD202350 ; National Natural Science Foundation of China (National Science Foundation of China)[32371289] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:001630170700001 |
| 出版者 | NATURE PORTFOLIO |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322166]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Hattori, Motoyuki; Liu, Hong; Yu, Ye |
| 作者单位 | 1.Lingang Lab, Shanghai, Peoples R China 2.Nanjing Univ Chinese Med, Hosp Integrated Tradit Chinese & Western Med, Nanjing, Peoples R China 3.Univ Chinese Acad Sci, Beijing, Peoples R China 4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Key Lab Glyco drug Res Zhejiang Prov, Hangzhou, Peoples R China 5.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China 6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China 7.Fudan Univ, Collaborat Innovat Ctr Genet & Dev, Sch Life Sci,Dept Physiol & Neurobiol, State Key Lab Genet & Dev Complex Phenotypes, Shanghai 200438, Peoples R China 8.China Pharmaceut Univ, Sch Tradit Chinese Pharm, Nanjing, Peoples R China 9.China Pharmaceut Univ, State Key Lab Nat Med, Nanjing, Peoples R China 10.China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Nanjing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Guo, Chang-Run,Sheng, Danqi,Li, Ji-Yuan,et al. Understanding interspecies drug response variations between human and rodent P2X7 receptors[J]. NATURE COMMUNICATIONS,2025,16(1):20. |
| APA | Guo, Chang-Run.,Sheng, Danqi.,Li, Ji-Yuan.,Li, Tian-Tian.,Yao, Jia-Bao.,...&Yu, Ye.(2025).Understanding interspecies drug response variations between human and rodent P2X7 receptors.NATURE COMMUNICATIONS,16(1),20. |
| MLA | Guo, Chang-Run,et al."Understanding interspecies drug response variations between human and rodent P2X7 receptors".NATURE COMMUNICATIONS 16.1(2025):20. |
入库方式： OAI收割
来源：上海药物研究所
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