Structure-based design of non-hypertrophic apelin receptor modulator.
Cell
; 187(6): 1460-1475.e20, 2024 Mar 14.
Article
in En
| MEDLINE
| ID: mdl-38428423
ABSTRACT
Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the ß-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cardiovascular Agents
/
Drug Design
/
Apelin Receptors
Limits:
Humans
Language:
En
Journal:
Cell
Year:
2024
Document type:
Article
Affiliation country:
Slovenia
Country of publication:
United States