Structure-based design of non-hypertrophic apelin receptor modulator

  • Cell. 2024 Mar 14;187(6):1460-1475.e20. doi: 10.1016/j.cell.2024.02.004.
Wei-Wei Wang  1 ,  Su-Yu Ji  1 ,  Wenjia Zhang  2 ,  Junxia Zhang  3 ,  Chenxi Cai  4 ,  Rubi Hu  4 ,  Shao-Kun Zang  5 ,  Luwei Miao  5 ,  Haomang Xu  1 ,  Li-Nan Chen  5 ,  Zongkuai Yang  6 ,  Jia Guo  5 ,  Jiao Qin  5 ,  Dan-Dan Shen  5 ,  Ping Liang  6 ,  Yan Zhang  7 ,  Yan Zhang  8
Affiliations
  • 1. Department of Pharmacology and Department of Pathology of Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; Center for Structural Pharmacology and Therapeutics Development, Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
  • 2. State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China; Haihe Laboratory of Cell Ecosystem, Beijing 100191, China.
  • 3. Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China; Haihe Laboratory of Cell Ecosystem, Beijing 100191, China; Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing 100191, China.
  • 4. Department of Pharmacology and Department of Pathology of Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 5. Department of Pharmacology and Department of Pathology of Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China.
  • 6. Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China.
  • 7. State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China; Haihe Laboratory of Cell Ecosystem, Beijing 100191, China. Electronic address: [email protected].
  • 8. Department of Pharmacology and Department of Pathology of Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; Center for Structural Pharmacology and Therapeutics Development, Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: [email protected].
PMID: 38428423 DOI: 10.1016/j.cell.2024.02.004
Abstract

Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for Cardiovascular Disease. However, adverse effects through the β-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.

Keywords
apelin receptor; biased signaling transduction; cryo-EM structure; drug design; myocardial hypertrophy; side effects.