CARDIOPROTECTIVE EFFECT OF NOVEL INHIBITORS OF G-PROTEIN-COUPLED RECEPTOR KINASE 2 (GRK2).

EMILIANA ECHEVERRIA; VALERIA MARTINEZ; ALEJANDRO CIOCCI PARDO; FANTINELLI, JULIANA C; SONIA RIPOLL; LORENA ACEVEDO; FEDERICO MONCZOR; CARLOS DAVIO; CARINA SHAYO; JAVIER RAMIREZ; ALEJANDRO AIELLO; VERONICA DEGIUSTTI; NATALIA C. FERNÁNDEZ

Congreso; LXVIII Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2023

GRK2 activity has been validated as a promising target for cardiovascular diseases, the major global causes of death. Via virtual screening and cell-based assays, we identified commercial molecules that inhibit GRK2's RGS homology domain (RH). Based on that, we developed novel analogues, L96B and L94C that were synthesized and tested as GRK2 inhibitors. This study aimed to preclinically characterized these analogues’ mechanism of action and potential therapeutic effectiveness.L94C and L96B inhibited interaction of GRK2 with G protein as observed in translocation and co-immunoprecipitation assay (61.3±0.4% and 49.9±0.6% of vehicle control (vc) respectively). They also inhibited desensitization of adrenergic receptors in HEK transfected cells in the nM range (EC50L94C=250nM, EC50L96B=20nM). In primary cultures of cardiomyocytes obtained from neonatal rats, we observed an enhanced response to isoproterenol (42.2±1.4% of vc for L94C and 64.3±1.4% of vc for L96B). Assays performed in male Wistar rat hearts subjected to Langendorff perfusion system showed that L94C and L96B at 100nM improved post-ischemic myocardial function recovery where LVDP, +dP/dtmax, and -dP/dtmax reached 40% to 60% of baseline values after reperfusion in comparison with 10-20% recovery in vc (p