Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors
文献类型：期刊论文
| 作者 | Gu, Yi-min1,2; Yuan, Qing-ning3; Li, Xin1,2; He, Qian1,2; Xu, H. Eric1,2; Zhao, Li-hua3 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2025-08-22 |
| 页码 | 11 |
| 关键词 | cagrilintide cryo-EM structure dual agonist amylin receptor calcitonin receptor obesity therapeutics |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-025-01635-2 |
| 英文摘要 | The global obesity epidemic and its associated metabolic disorders urgently require more effective therapeutic interventions, particularly multi-pathway targeting therapies. Cagrilintide (Cagri), functioning as a dual amylin receptor (AMYRs) and calcitonin receptor (CTR) agonist (DACRA), demonstrates significant efficacy in obesity treatment, although its structural activation mechanism remains unclear. This study elucidates the non-selective activation mechanism by determining cryo-EM structures of Cagri bound to AMY1R-Gs and CTR-Gs complexes. Cagri adopts similar "bypass" binding modes in both receptors, which is distinct from other existing DACRAs that primarily achieve extended half-life through N-terminal lipid modification. Key molecular features include the F23Cagri residue anchoring the peptide at the receptor transmembrane (TM) bundle level and the micelle, an E14-R17 intramolecular salt bridge enhancing helical stability, and C-terminal P37Cagri interaction with the receptor ECD. These features collectively enable non-specific binding and activation across different receptors. Both structural and functional analyses revealed Cagri's non-selective activation of Gs signaling pathways through CTR and AMY1R. These findings provide a comprehensive structural framework for developing next-generation anti-obesity drugs based on dual receptor activation mechanisms. |
| WOS关键词 | ONCE-WEEKLY CAGRILINTIDE ; SEMAGLUTIDE 2.4 MG ; WEIGHT MANAGEMENT ; DOUBLE-BLIND ; MULTICENTER ; SAFETY ; RAMPS |
| 资助项目 | Chinese Academy of Sciences ; National Natural Science Foundation of China[32371255] ; National Natural Science Foundation of China[32071203] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82404881] ; Natural Science Foundation of Shanghai[23ZR1475200] ; National Key R&D Program of China[2022YFC2703105] ; National Key R&D Program of China[2019YFA0904200] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Young Innovator Association of CAS[Y2022078] ; Young Innovator Association of CAS[LG-GG-202204-01] ; State Key Laboratory of Drug Research[SKLDR-2023-TT-04] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001555472300001 |
| 出版者 | NATURE PUBL GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321300]  |
| 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 | Xu, H. Eric; Zhao, Li-hua |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Shanghai Jiao Tong Univ, Res Ctr Med Struct Biol, Natl Res Ctr Translat Med Shanghai, State Key Lab Med Genom,Ruijin Hosp,Sch Med, Shanghai 200025, Peoples R China |
| 推荐引用方式 GB/T 7714 | Gu, Yi-min,Yuan, Qing-ning,Li, Xin,et al. Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors[J]. ACTA PHARMACOLOGICA SINICA,2025:11. |
| APA | Gu, Yi-min,Yuan, Qing-ning,Li, Xin,He, Qian,Xu, H. Eric,&Zhao, Li-hua.(2025).Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors.ACTA PHARMACOLOGICA SINICA,11. |
| MLA | Gu, Yi-min,et al."Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors".ACTA PHARMACOLOGICA SINICA (2025):11. |
入库方式： OAI收割
来源：上海药物研究所
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