title: Discovery and cardioprotective effects of the first non-Peptide agonists of the G protein-coupled prokineticin receptor-1.
abstract: Prokineticins are angiogenic hormones that activate two G protein-coupled receptors: PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. Identification of non-peptide PKR1 agonists that contribute to myocardial repair and collateral vessel growth hold promises for treatment of heart diseases. Through a combination of in silico studies, medicinal chemistry, and pharmacological profiling approaches, we designed, synthesized, and characterized the first PKR1 agonists, demonstrating their cardioprotective activity against myocardial infarction (MI) in mice. Based on high throughput docking protocol, 250,000 compounds were computationally screened for putative PKR1 agonistic activity, using a homology model, and 10 virtual hits were pharmacologically evaluated. One hit internalizes PKR1, increases calcium release and activates ERK and Akt kinases. Among the 30 derivatives of the hit compound, the most potent derivative, IS20, was confirmed for its selectivity and specificity through genetic gain- and loss-of-function of PKR1. Importantly, IS20 prevented cardiac lesion formation and improved cardiac function after MI in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis. The preclinical investigation of the first PKR1 agonists provides a novel approach to promote cardiac neovasculogenesis after MI.
authors.affiliation: Biotechnology and Cell Signaling Laboratory (UMR 7242), CNRS-University of Strasbourg, Illkirch, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Gasser
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, Siena, Italy; Departments of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.affiliation: Biotechnology and Cell Signaling Laboratory (UMR 7242), CNRS-University of Strasbourg, Illkirch, France.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Urayama
authors.affiliation: Biotechnology and Cell Signaling Laboratory (UMR 7242), CNRS-University of Strasbourg, Illkirch, France; Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
authors.forename: Toshishide
authors.initials: T
authors.lastname: Nishi
authors.affiliation: Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurose
authors.affiliation: Departments of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tafi
authors.affiliation: Therapeutic Innovation Laboratory (UMR7200), CNRS-University of Strasbourg, Illkirch, France.
authors.forename: Nigel
authors.initials: N
authors.lastname: Ribeiro
authors.affiliation: Therapeutic Innovation Laboratory (UMR7200), CNRS-University of Strasbourg, Illkirch, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Désaubry
authors.affiliation: Biotechnology and Cell Signaling Laboratory (UMR 7242), CNRS-University of Strasbourg, Illkirch, France.
authors.forename: Canan G
authors.initials: CG
authors.lastname: Nebigil
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D019295:Computational Biology; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004452:Echocardiography; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D062105:Molecular Docking Simulation; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry; D020011:Protective Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001549:Benzamides; C525015:PKR1 protein, mouse; D010455:Peptides; D020011:Protective Agents; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D002118:Calcium
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