Discovery and cardioprotective effects of the first non-peptide agonists of the G protein-coupled prokineticin receptor-1

Adeline Gasser, Simone Brogi, Kyoji Urayama, Toshishide Nishi, Hitoshi Kurose, Andrea Tafi, Nigel Ribeiro, Laurent Désaubry, Canan G. Nebigil

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish
Article numbere0121027
JournalPloS one
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 1 2015

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Fingerprint Dive into the research topics of 'Discovery and cardioprotective effects of the first non-peptide agonists of the G protein-coupled prokineticin receptor-1'. Together they form a unique fingerprint.

  • Cite this

    Gasser, A., Brogi, S., Urayama, K., Nishi, T., Kurose, H., Tafi, A., Ribeiro, N., Désaubry, L., & Nebigil, C. G. (2015). Discovery and cardioprotective effects of the first non-peptide agonists of the G protein-coupled prokineticin receptor-1. PloS one, 10(4), [e0121027]. https://doi.org/10.1371/journal.pone.0121027