Structure-based design of non-hypertrophic apelin receptor modulator.

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.

Generation of a human induced pluripotent stem cell line from a hypertrophic cardiomyopathy patient carrying MYH6/c.611G>A mutation.

Hypertrophic cardiomyopathy (HCM), characterized by left ventricular hypertrophy and preserved or increased left ventricular ejection fraction, is the most common autosomal dominant inherited cardiovascular disease. We generated a human induced pluripotent stem cell (hiPSC) line derived from a HCM patient who carried a heterozygous missense mutation in the myosin heavy chain 6 (MYH6) gene. With a non-integrated Sendai viral method, the patient-specific hiPSCs were generated from skin fibroblasts. We confirmed the stemness of the hiPSCs and its capability of differentiating into three germ layers. Meanwhile, the generated hiPSCs showed human embryonic stem cell-like morphology and normal karyotype.