Solid-phase synthesis of heterobivalent ligands targeted to melanocortin and cholecystokinin receptors

Jatinder S. Josan, Josef Vagner, Heather L. Handl, Rajesh Sankaranarayanan, Robert J. Gillies, Victor J Hruby

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Heteromultivalency provides a route to increase binding avidity and to high specificity when compared to monovalent ligands. The enhanced specificity can potentially serve as a unique platform to develop diagnostics and therapeutics. To develop new imaging agents based upon multivalency, we employed heterobivalent constructs of optimized ligands. In this report, we describe synthetic methods we have developed for the preparation of heterobivalent constructs consisting of ligands targeted simultaneously to the melanocortin receptor, hMC4R, and the cholecystokinin receptors, CCK-2R. Modeling data suggest that a linker distance span of 20-50 Å is needed to crosslink these two G-protein coupled receptors (GPCRs). The two ligands were tethered with linkers of varying rigidity and length, and flexible polyethylene glycol based PEGO chain or semi-rigid [poly(Pro-Gly)] linkers were employed for this purpose. The described synthetic strategy provides a modular way to assemble ligands and linkers on solid-phase supports. Examples of heterobivalent ligands are provided to illustrate the increased binding avidity to cells that express the complementary receptors.

Original languageEnglish (US)
Pages (from-to)293-300
Number of pages8
JournalInternational Journal of Peptide Research and Therapeutics
Issue number4
StatePublished - Dec 2008


  • Heterobivalent ligands
  • Heterodimers
  • Linkers
  • Multivalency
  • Receptor combination approach
  • Solid-phase peptide synthesis
  • Targeted agents

ASJC Scopus subject areas

  • Analytical Chemistry
  • Bioengineering
  • Biochemistry
  • Molecular Medicine
  • Drug Discovery


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