Novel RANK Antagonists for the Treatment of Bone-Resorptive Disease: Theoretical Predictions and Experimental Validation

Authors

  • Stéphane Téletchéa,

    1. INSERM, UMR 957, Equipe labellisée LIGUE 2012, Université de Nantes, Laboratory of the Physiopathology of Bone Resorption and Therapy of Primary Bone Tumors (LPRO), Nantes, France
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    • The first two authors contributed equally to this work.
  • Verena Stresing,

    1. INSERM, UMR 957, Equipe labellisée LIGUE 2012, Université de Nantes, Laboratory of the Physiopathology of Bone Resorption and Therapy of Primary Bone Tumors (LPRO), Nantes, France
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    • The first two authors contributed equally to this work.
  • Soizic Hervouet,

    1. INSERM, UMR 957, Equipe labellisée LIGUE 2012, Université de Nantes, Laboratory of the Physiopathology of Bone Resorption and Therapy of Primary Bone Tumors (LPRO), Nantes, France
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  • Marc Baud'huin,

    1. INSERM, UMR 957, Equipe labellisée LIGUE 2012, Université de Nantes, Laboratory of the Physiopathology of Bone Resorption and Therapy of Primary Bone Tumors (LPRO), Nantes, France
    2. Nantes Hospital, Nantes, France
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  • Marie-Françoise Heymann,

    1. INSERM, UMR 957, Equipe labellisée LIGUE 2012, Université de Nantes, Laboratory of the Physiopathology of Bone Resorption and Therapy of Primary Bone Tumors (LPRO), Nantes, France
    2. Nantes Hospital, Nantes, France
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  • Gildas Bertho,

    1. CNRS UMR8601, Université Paris Descartes, Paris, France
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  • Céline Charrier,

    1. INSERM, UMR 957, Equipe labellisée LIGUE 2012, Université de Nantes, Laboratory of the Physiopathology of Bone Resorption and Therapy of Primary Bone Tumors (LPRO), Nantes, France
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  • Kosei Ando,

    1. INSERM, UMR 957, Equipe labellisée LIGUE 2012, Université de Nantes, Laboratory of the Physiopathology of Bone Resorption and Therapy of Primary Bone Tumors (LPRO), Nantes, France
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  • Dominique Heymann

    Corresponding author
    1. INSERM, UMR 957, Equipe labellisée LIGUE 2012, Université de Nantes, Laboratory of the Physiopathology of Bone Resorption and Therapy of Primary Bone Tumors (LPRO), Nantes, France
    2. Nantes Hospital, Nantes, France
    • Address correspondence to: Dominique Heymann, PhD, INSERM, UMR 957, Faculté de Médecine, Université de Nantes, 1 Rue Gaston Veil, 44035 Nantes, France. E-mail: dominique.heymann@univ-nantes.fr

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ABSTRACT

Receptor activator of nuclear factor-κB (RANK) and RANK ligand (RANKL) play a pivotal role in bone metabolism, and selective targeting of RANK signaling has become a promising therapeutic strategy in the management of resorptive bone diseases. Existing antibody-based therapies and novel inhibitors currently in development were designed to target the ligand, rather than the membrane receptor expressed on osteoclast precursors. We describe here an alternative approach to designing small peptides able to specifically bind to the hinge region of membrane RANK responsible for the conformational change upon RANKL association. A nonapeptide generated by this method was validated for its biological activity in vitro and in vivo and served as a lead compound for the generation of a series of peptide RANK antagonists derived from the original sequence. Our study presents a structure- and knowledge-based strategy for the design of novel effective and affordable small peptide inhibitors specifically targeting the receptor RANK and opens a new therapeutic opportunity for the treatment of resorptive bone disease. © 2014 American Society for Bone and Mineral Research.

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