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Novel RANK Antagonists for the Treatment of Bone‐Resorptive Disease: Theoretical Predictions and Experimental Validation
Author(s) -
Téletchéa Stéphane,
Stresing Verena,
Hervouet Soizic,
Baud'huin Marc,
Heymann MarieFrançoise,
Bertho Gildas,
Charrier Céline,
Ando Kosei,
Heymann Dominique
Publication year - 2014
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.2170
Subject(s) - rank (graph theory) , medicine , disease , mathematics , combinatorics
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.