Teletchea, S., Stresing, V., Hervouet, S. et al. (6 more authors) (2014) Novel RANK Antagonists for the Treatment of Bone-Resorptive Disease: Theoretical Predictions and Experimental Validation. Journal of Bone and Mineral Research, 29 (6). pp. 1466-1477. ISSN 0884-0431
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2014 American Society for Bone and Mineral Research |
Keywords: | BONE RESORPTION; DRUG DESIGN; RANK; RANKL; PEPTIDE INHIBITORS |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 28 Apr 2016 13:48 |
Last Modified: | 28 Apr 2016 13:53 |
Published Version: | http://dx.doi.org/10.1002/jbmr.2170 |
Status: | Published |
Publisher: | American Society for Bone and Mineral Research |
Refereed: | Yes |
Identification Number: | 10.1002/jbmr.2170 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:98158 |