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

22 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

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Endocrine-Gland-Derived Vascular Endothelial Growth Factor
cardioprotective effect
myocardial infarction
G-Protein-Coupled Receptors
GTP-Binding Proteins
agonists
Myocardial Infarction
Derivatives
chemical derivatives
Repair
Phosphotransferases
Pharmaceutical Chemistry
mice
Throughput
heart diseases
Hormones
cardiac output
Calcium
mitogen-activated protein kinase
Computer Simulation

All Science Journal Classification (ASJC) codes

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

Cite this

Discovery and cardioprotective effects of the first non-peptide agonists of the G protein-coupled prokineticin receptor-1. / Gasser, Adeline; Brogi, Simone; Urayama, Kyoji; Nishi, Toshishide; Kurose, Hitoshi; Tafi, Andrea; Ribeiro, Nigel; Désaubry, Laurent; Nebigil, Canan G.

In: PloS one, Vol. 10, No. 4, e0121027, 01.04.2015.

Research output: Contribution to journalArticle

Gasser, A, Brogi, S, Urayama, K, Nishi, T, Kurose, H, Tafi, A, Ribeiro, N, Désaubry, L & Nebigil, CG 2015, 'Discovery and cardioprotective effects of the first non-peptide agonists of the G protein-coupled prokineticin receptor-1', PloS one, vol. 10, no. 4, e0121027. https://doi.org/10.1371/journal.pone.0121027
Gasser, Adeline ; Brogi, Simone ; Urayama, Kyoji ; Nishi, Toshishide ; Kurose, Hitoshi ; Tafi, Andrea ; Ribeiro, Nigel ; Désaubry, Laurent ; Nebigil, Canan G. / Discovery and cardioprotective effects of the first non-peptide agonists of the G protein-coupled prokineticin receptor-1. In: PloS one. 2015 ; Vol. 10, No. 4.
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