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

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  • Jingbo Xiao

    (NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health)

  • Zaohua Huang

    (Herbert Wertheim College of Medicine, Florida International University)

  • Catherine Z. Chen

    (NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health)

  • Irina U. Agoulnik

    (Herbert Wertheim College of Medicine, Florida International University)

  • Noel Southall

    (NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health)

  • Xin Hu

    (NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health)

  • Raisa E. Jones

    (NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health)

  • Marc Ferrer

    (NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health)

  • Wei Zheng

    (NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health)

  • Alexander I. Agoulnik

    (Herbert Wertheim College of Medicine, Florida International University)

  • Juan J. Marugan

    (NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health)

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.

Suggested Citation

  • 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, 2013. "Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1," Nature Communications, Nature, vol. 4(1), pages 1-7, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2953
    DOI: 10.1038/ncomms2953
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