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

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.
Type de document :
Article dans une revue
Journal of Bone and Mineral Research, American Society for Bone and Mineral Research, 2014, 29 (6), pp.1466 - 1477. 〈10.1002/jbmr.2170〉
Liste complète des métadonnées

Littérature citée [61 références]  Voir  Masquer  Télécharger

http://www.hal.inserm.fr/inserm-01644748
Contributeur : Dominique Heymann <>
Soumis le : mercredi 22 novembre 2017 - 15:24:15
Dernière modification le : jeudi 5 avril 2018 - 10:36:48

Identifiants

Collections

Citation

Stéphane Téletchéa, Verena Stresing, Soizic Hervouet, Marc Baud'Huin, Marie-Françoise Heymann, et al.. Novel RANK Antagonists for the Treatment of Bone-Resorptive Disease: Theoretical Predictions and Experimental Validation. Journal of Bone and Mineral Research, American Society for Bone and Mineral Research, 2014, 29 (6), pp.1466 - 1477. 〈10.1002/jbmr.2170〉. 〈inserm-01644748〉

Partager

Métriques

Consultations de la notice

83

Téléchargements de fichiers

69