Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1

Jingbo Xiao, Zaohua Huang, Catherine Z. Chen, Irina U. Agoulnik, Noel Southall, Xin Hu, Raisa E. Jones, Marc Ferrer, Wei Zheng, Alexander I. Agoulnik, Juan J. Marugan

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

The anti-fibrotic, vasodilatory and pro-angiogenic therapeutic properties of recombinant relaxin peptide hormone have been investigated in several diseases, and recent clinical trial data has shown benefit in treating acute heart failure. However, the remodelling capacity of these peptide hormones is difficult to study in chronic settings because of their short half-life and the need for intravenous administration. Here we present the first small-molecule series of human relaxin/insulin-like family peptide receptor 1 agonists. These molecules display similar efficacy as the natural hormone in several functional assays. Mutagenesis studies indicate that the small molecules activate relaxin receptor through an allosteric site. These compounds have excellent physical and in vivo pharmacokinetic properties to support further investigation of relaxin biology and animal efficacy studies of the therapeutic benefits of relaxin/insulin-like family peptide receptor 1 activation.

Original languageEnglish (US)
Article number1953
JournalNature communications
Volume4
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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