Design, synthesis, and biological studies of efficient multivalent melanotropin ligands: Tools toward melanoma diagnosis and treatment

Nabila Brabez, Ronald M. Lynch, Liping Xu, Robert J. Gillies, Gerard Chassaing, Solange Lavielle, Victor J. Hruby

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7375-7384
Number of pages10
JournalJournal of Medicinal Chemistry
Volume54
Issue number20
DOIs
StatePublished - Oct 27 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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