title: 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.
authors.affiliation: 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.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Téletchéa
authors.forename: Verena
authors.initials: V
authors.lastname: Stresing
authors.forename: Soizic
authors.initials: S
authors.lastname: Hervouet
authors.forename: Marc
authors.initials: M
authors.lastname: Baud'huin
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Heymann
authors.forename: Gildas
authors.initials: G
authors.lastname: Bertho
authors.forename: Céline
authors.initials: C
authors.lastname: Charrier
authors.forename: Kosei
authors.initials: K
authors.lastname: Ando
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010052:Ovariectomy; D010455:Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D053245:RANK Ligand / Q000494:pharmacology; D011859:Radiography; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D010455:Peptides; D020011:Protective Agents; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B
keywords: BONE RESORPTION; DRUG DESIGN; PEPTIDE INHIBITORS; RANK; RANKL