Cell-specific targeting by heterobivalent ligands

Jatinder S. Josan, Heather L. Handl, Rajesh Sankaranarayanan, Liping Xu, Ronald M. Lynch, Josef Vagner, Eugene A. Mash, Victor J. Hruby, Robert J. Gillies

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Abstract

Current cancer therapies exploit either differential metabolism or targeting to specific individual gene products that are overexpressed in aberrant cells. The work described herein proposes an alternative approach - to specifically target combinations of cell-surface receptors using heteromultivalent ligands ("receptor combination approach"). As a proof-of-concept that functionally unrelated receptors can be noncovalently cross-linked with high avidity and specificity, a series of heterobivalent ligands (htBVLs) were constructed from analogues of the melanocortin peptide ligand ([Nle 4, dPhe 7]-α-MSH) and the cholecystokinin peptide ligand (CCK-8). Binding of these ligands to cells expressing the human Melanocortin-4 receptor and the Cholecystokinin-2 receptor was analyzed. The MSH(7) and CCK(6) were tethered with linkers of varying rigidity and length, constructed from natural and/or synthetic building blocks. Modeling data suggest that a linker length of 20 - 50 Å is needed to simultaneously bind these two different G-protein coupled receptors (GPCRs). These ligands exhibited up to 24-fold enhancement in binding affinity to cells that expressed both (bivalent binding), compared to cells with only one (monovalent binding) of the cognate receptors. The htBVLs had up to 50-fold higher affinity than that of a monomeric CCK ligand, i.e., Ac-CCK(6)-NH 2. Cell-surface targeting of these two cell types with labeled heteromultivalent ligand demonstrated high avidity and specificity, thereby validating the receptor combination approach. This ability to noncovalently cross-link heterologous receptors and target individual cells using a receptor combination approach opens up new possibilities for specific cell targeting in vivo for therapy or imaging.

Original languageEnglish (US)
Pages (from-to)1270-1278
Number of pages9
JournalBioconjugate Chemistry
Volume22
Issue number7
DOIs
StatePublished - Jul 20 2011

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ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

Cite this

Josan, J. S., Handl, H. L., Sankaranarayanan, R., Xu, L., Lynch, R. M., Vagner, J., Mash, E. A., Hruby, V. J., & Gillies, R. J. (2011). Cell-specific targeting by heterobivalent ligands. Bioconjugate Chemistry, 22(7), 1270-1278. https://doi.org/10.1021/bc1004284