Abstract: Apelin receptor (APLNR) is a crucial G protein-coupled receptor that plays a central role in cardiovascular homeostasis; therefore, it represents a promising therapeutic target for heart failure, myocardial infarction, cardiac hypertrophy, and pulmonary arterial hypertension. However, the activation of APLNR simultaneously engages inhibitory G protein (G_i)-mediated protective signaling and β-arrestin pathways that are associated with pathological cardiac remodeling, thereby imposing significant limitations and challenges for the therapeutic development of conventional balanced agonists. Recent advances in structural biology and pharmacology have provided valuable mechanistic insights into receptor activation and biased signaling. High-resolution cryo-electron microscopy (cryo-EM) structures revealed the conformational basis of signal bias, enabling the rational design of fully G protein-biased agonists that retain cardiovascular benefits while avoiding hypertrophic effects. This review summarizes recent progress in APLNR signaling mechanisms and biased ligand development, highlighting a number of emerging strategies for the precision pharmacological targeting of this receptor.

基于结构开发用于心血管疾病治疗的G蛋白偏向性apelin受体激动剂

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