title: Design, synthesis, and biological studies of efficient multivalent melanotropin ligands: tools toward melanoma diagnosis and treatment.
abstract: To achieve early detection and specific cancer treatment, we propose the use of multivalent interactions in which a series of binding events leads to increased affinity and consequently to selectivity. Using melanotropin (MSH) ligands, our aim is to target melanoma cells which overexpress melanocortin receptors. In this study, we report the design and efficient synthesis of new trivalent ligands bearing MSH ligands. Evaluation of these multimers on a cell model engineered to overexpress melanocortin 4 receptors (MC4R) showed up to a 350-fold increase in binding compared to the monomer, resulting in a trivalent construct with nanomolar affinity starting from a micromolar affinity ligand. Cyclic adenosine monophosphate (cAMP) production was also investigated, leading to more insights into the effects of multivalent compounds on transduction mechanisms.
authors.affiliation: UPMC Paris06, UMR 7203, Laboratoire des BioMolécules, Université P. et M. Curie, 75005 Paris France.
authors.forename: Nabila
authors.initials: N
authors.lastname: Brabez
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Lynch
authors.forename: Liping
authors.initials: L
authors.lastname: Xu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gillies
authors.forename: Gerard
authors.initials: G
authors.lastname: Chassaing
authors.forename: Solange
authors.initials: S
authors.lastname: Lavielle
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D001667:Binding, Competitive; D000242:Cyclic AMP / Q000378:metabolism; D050091:Dendrimers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism*; D008545:Melanoma / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D013329:Structure-Activity Relationship
chemical_list: D050091:Dendrimers; D008024:Ligands; D010455:Peptides; D044105:Receptor, Melanocortin, Type 4; D009074:Melanocyte-Stimulating Hormones; D000242:Cyclic AMP