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

IF 9.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-05-02 DOI:10.1073/pnas.2423432122

Qiu Sun, Xiaowen Tian, Lun Tan, Yan Deng, Sicen Liu, Yixiao Xiong, Yuying Feng, Yujia Wang, Lele Zhang, Jiayi Zhu, Huan Xiao, Zhenhua Shao, Yingqiang Guo, Wei Yan, Tao Li, Liang Ouyang

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引用次数: 0

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).

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多尺度偏置化学空间重构用于开发具有抗hfpef功效的APLNR激动剂

保留射血分数的心力衰竭（HFpEF）是一个重大的全球健康负担，但有效的药物治疗仍然难以捉摸。血管紧张素样1受体，也被称为apelin受体（APLNR），由于其在调节心血管功能中的作用，是治疗HFpEF的一个有希望的靶点。尽管内源性配体apelin具有心脏保护作用，但实现g蛋白偏向激动作用的治疗效果仍是一个重大挑战。在这项研究中，我们揭示了由部分G蛋白偏倚的APLNR激动剂CMF-019介导的偏倚信号转导途径，并开发了一种偏倚化学空间重塑方法来鉴定针对APLNR的特异性G蛋白偏倚激动剂。这些激动剂在体外和体内均表现出增强的gi蛋白偏向功能和保护作用。我们的发现不仅增强了对aplnr偏倚激动作用的理解，而且还建立了用于修饰和重塑其他g蛋白偶联受体（gpcr）偏倚化学景观的药物设计策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Proceedings of the National Academy of Sciences of the United States of America 综合性期刊-综合性期刊

CiteScore

19.00

自引率

0.90%

发文量

3575

审稿时长

2.5 months

期刊介绍： The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.