Multiscale biased chemical space remodeling for developing APLNR agonists with anti-HFpEF efficacy
Abstract
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 i -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).
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Qiu Sun
Department of Cardiovascular Surgery, Cardiovascular Surgery Research Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University
Xiaowen Tian
Lun Tan
Department of Cardiovascular Surgery, Cardiovascular Surgery Research Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University
Yan Deng
Department of Cardiovascular Surgery, Cardiovascular Surgery Research Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University
Sicen Liu
Department of Cardiovascular Surgery, Cardiovascular Surgery Research Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University
Yixiao Xiong
Department of Cardiovascular Surgery, Cardiovascular Surgery Research Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University
Yuying Feng
Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University
Yujia Wang
Lele Zhang
Jiayi Zhu
Institute of Translational Medicine, Shanghai Engineering Research Center of Organ Repair, Shanghai University
Huan Xiao
Zhenhua Shao
Yingqiang Guo
Department of Cardiovascular Surgery, Cardiovascular Surgery Research Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University
Wei Yan
Tao Li
Liang Ouyang
Department of Cardiovascular Surgery, Cardiovascular Surgery Research Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University