Multiscale biased chemical space remodeling for developing APLNR agonists with anti-HFpEF efficacy
Heart failure with preserved ejection fraction (HFpEF) represents a significant global health burden, yet effective pharmacotherapies remain elusive. The angiotensin-like 1 receptor, also known as the apelin receptor (APLNR), is a promising target for treating HFpEF due to its role in modulating cardiovascular function. Despite the cardioprotective effects of endogenous ligand, apelin, achieving G-protein-biased agonism for therapeutic benefit poses a significant challenge. In this study, we unravel the biased signal transduction pathway mediated by a reported partial G<sub>i</sub>-protein-biased APLNR agonist CMF-019 and developed a biased chemical space remodeling approach to identify exclusive G-protein-biased agonists targeting APLNR. These agonists exhibited enhanced Gi-protein-biased function and protective effects in both in vitro and in vivo. Our findings not only enhance comprehension of APLNR-biased agonism but also establish drug design strategies for modifying and reshaping biased chemical landscapes in other G-protein-coupled receptors (GPCRs).
Authors
- Zhenhua Shao (ORCID: https://orcid.org/0000-0001-7204-801X)
- Liang Ouyang (ORCID: https://orcid.org/0000-0001-5537-8834)
- Yuying Feng (ORCID: https://orcid.org/0000-0002-0581-2476)
- Yan Deng (ORCID: https://orcid.org/0000-0002-1179-9896)
- Yixiao Xiong (ORCID: https://orcid.org/0000-0002-8864-8076)
- Qiu Sun (ORCID: https://orcid.org/0000-0001-5122-2226)
- Wei Yan (ORCID: https://orcid.org/0000-0001-9569-9026)
- Yingqiang Guo (ORCID: https://orcid.org/0000-0002-3347-1680)
- Tao Li (ORCID: https://orcid.org/0000-0002-7988-3090)
- Lun Tan (ORCID: https://orcid.org/0000-0002-9152-6846)
- Lele Zhang (ORCID: https://orcid.org/0000-0002-5595-3103)
- Yujia Wang (ORCID: https://orcid.org/0009-0009-1725-5839)
- Xiaowen Tian
- Jiayi Zhu (ORCID: https://orcid.org/0009-0000-0428-4512)
- Huan Xiao (ORCID: https://orcid.org/0000-0002-3931-3667)
- Sicen Liu (ORCID: https://orcid.org/0000-0001-6906-6233)
Institutions
- Shanghai University (CN)
- Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
- State Key Laboratory of Biotherapy
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-05-02
- DOI
- https://doi.org/10.1073/pnas.2423432122
- Citations
- 1
- Primary Topic
- Apelin-related biomedical research
- Type
- article
- Field-Weighted Citation Impact
- 1.39
Funders
- National Natural Science Foundation of China