Multiscale biased chemical space remodeling for developing APLNR agonists with anti-HFpEF efficacy

• 成果类型: Article
• 署名作者: Sun, Qiu; Tian, Xiaowen; Tan, Lun; Deng, Yan; Liu, Sicen; Xiong, Yixiao; Feng, Yuying; Wang, Yujia; Zhang, Lele; Zhu, Jiayi; Xiao, Huan; Shao, Zhenhua; Guo, Yingqiang; Yan, Wei; Li, Tao; Ouyang, Liang
• 署名单位: Sichuan University; Sichuan University; Sichuan University; Sichuan University; Shanghai University; Tianfu Jincheng Laboratory
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9893
• DOI: 10.1073/pnas.2423432122
• 发表日期: 2025-05-06
• 关键词: heart-failure; apelin

摘要

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 Gi-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).