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

Area of Science:

• Cardiovascular pharmacology
• G-protein-coupled receptor (GPCR) signaling

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a major health issue with limited treatment options.
• The apelin receptor (APLNR) is a potential therapeutic target for HFpEF, influenced by its endogenous ligand, apelin.
• Achieving G-protein-biased agonism at APLNR for therapeutic advantage is challenging.

Purpose of the Study:

• To investigate the biased signal transduction pathway of a partial G_i-protein-biased APLNR agonist, CMF-019.
• To develop a novel chemical space remodeling approach for identifying exclusive G-protein-biased APLNR agonists.
• To evaluate the therapeutic potential of these novel agonists in HFpEF.

Main Methods:

• Utilized a biased chemical space remodeling strategy to discover new APLNR agonists.
• Assessed the G-protein-biased signaling profiles of identified agonists.
• Validated the efficacy of these agonists in vitro and in vivo models relevant to HFpEF.

Main Results:

• Successfully identified exclusive G-protein-biased agonists targeting APLNR.
• These novel agonists demonstrated enhanced G_i-protein-biased signaling.
• Demonstrated significant protective effects in both in vitro and in vivo experimental systems.

Conclusions:

• The study enhances the understanding of APLNR-biased agonism mechanisms.
• Established effective drug design strategies for developing biased agonists for APLNR.
• Provides a framework for reshaping biased chemical landscapes in other GPCR targets for therapeutic applications.