0365: Non-peptidic prokineticin receptor 1 agonist as a novel cardioprotective therapeutic

Abstract

Objective Prokineticins are potent angiogenic peptides that bind to two G protein-coupled receptors to initiate their biological effects. We previously have shown that prokineticin receptor-1 (PKR1) signaling contributes to cardiomyocyte survival or repair in myocardial infarction. Here, we discovered the first non-peptidic PKR1 agonists and examined their effects in mice model of heart diseases. Methods and results Herein we identify a selective PKR1 agonist both in vitro and in vivo, utilizing GPCR structure-based virtual screening approach. High Throughput Docking was carried out by GOLD using homology model of PKR1. Asinex gold collection 3D chemical databese (250,000 compounds) was screened by the docking protocol. We provided a strategy with a high potential for in silico identifying one agonist hit. We present here IS20, the first synthetic PKR1 agonist that induces angiogenesis in the presence of PKR1 on the endothelial cells seeded on matrigel. IS20 reduced doxorubicin cytotoxicity in H9C2 cells. IS20 promotes mouse epicardial progenitor cell differentiation into endothelial cells. In vivo IS20 activates Akt in mice heart. IS20 treatment of mice after coronary ligation reduces mortality by 30%. Conclusion This study identifies a non-peptidic PKR1 agonist as therapeutic target holding promise for treatment of heart diseases.