De novo design of protein condensation inhibitors by targeting an allosteric site of cGAS
文献类型：期刊论文
| 作者 | Zhao, Wenfeng5; Chen, Guofeng4; He, Jian3,5; Shen, Xiaofang2,5; Xiong, Muya4; Xiong, Liwei3,4,5; Qi, Zhihao3,4,5; Xie, Hang5; Li, Wanchen5; Li, Jiameng5 |
| 刊名 | NATURE COMMUNICATIONS
 |
| 出版日期 | 2025-06-03 |
| 卷号 | 16期号:1页码:20 |
| DOI | 10.1038/s41467-025-60297-0 |
| 英文摘要 | Cyclic GMP-AMP synthase (cGAS), a key mediator of the cGAS-STING DNA sensing pathway that triggers type-I interferon responses, plays a crucial role in innate immunity and has been implicated in the pathogenesis of various disease. Despite advances in the development of cGAS inhibitors, none have reached the market and there remains an unmet need for divergent chemical scaffolds with high selectivity, potency across species, and target-adaptive mechanisms of action to explore cGAS's potential as a therapeutic target. Here we report the structural, biochemical, cellular, and mechanistic characterization of the XL series of allosteric inhibitors, designed to engage an innovative allosteric site near the activation loop of cGAS. Among them, XL-3156 and XL-3158 emerge as potent, selective, cross-species cGAS inhibitors that simultaneously occupy allosteric and orthosteric sites, stabilizing the activation loop in a closed, inactive conformation and thereby attenuating the cGAS-DNA interactions. Moreover, these allosteric inhibitors, also known as protein condensation inhibitors (PCIs), significantly suppress cGAS-DNA condensate formation, triggering a morphological transition from liquid-solid phase separation (LSPS) to liquid-liquid phase separation (LLPS) at the molecular level while eliminating LLPS in cells. The distinct mechanism of action enables PCIs to achieve synergistic effects in combination with orthosteric inhibitors. These results establish a mechanism-driven pharmacological strategy to inhibit cGAS through PCIs that modulate phase separation primarily by engagement of the allosteric site. |
| WOS关键词 | CYCLIC GMP-AMP ; PHASE-SEPARATION ; SYNTHASE ; 2ND-MESSENGER ; ACTIVATION ; PARAMETERS ; SERUM ; MODEL ; AMBER |
| 资助项目 | This work was supported by the National Key RD Program of China (No. 2023YFF1205104), the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDB0830000), and Research Program of Shanghai Institute of Materia Medica, Chinese Academ ; Institutional Technology Service Center of Shanghai Institute of Materia Medica[2023YFF1205104] ; National Key R&D Program of China[XDB0830000] ; Chinese Academy of Sciences[SIMM0320231006] ; Research Program of Shanghai Institute of Materia Medica, Chinese Academy of Sciences |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:001502176100020 |
| 出版者 | NATURE PORTFOLIO |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318282]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhao, Wenfeng; Xu, Yechun |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai, Peoples R China 2.China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, State Key Lab Nat 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, Hangzhou, Peoples R China 5.Univ Chinese Acad Sci, Shanghai Inst Materia Med, State Key Lab Drug Res, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhao, Wenfeng,Chen, Guofeng,He, Jian,et al. De novo design of protein condensation inhibitors by targeting an allosteric site of cGAS[J]. NATURE COMMUNICATIONS,2025,16(1):20. |
| APA | Zhao, Wenfeng.,Chen, Guofeng.,He, Jian.,Shen, Xiaofang.,Xiong, Muya.,...&Xu, Yechun.(2025).De novo design of protein condensation inhibitors by targeting an allosteric site of cGAS.NATURE COMMUNICATIONS,16(1),20. |
| MLA | Zhao, Wenfeng,et al."De novo design of protein condensation inhibitors by targeting an allosteric site of cGAS".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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