Cell-specific targeting by heterobivalent ligands

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

Research output: Contribution to journalArticle

35 Citations (Scopus)

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

Fingerprint

Ligands
Melanocyte-Stimulating Hormones
Peptides
Melanocortins
Cholecystokinin B Receptor
Sincalide
Cholecystokinin
Cell Surface Receptors
G-Protein-Coupled Receptors
Metabolism
Rigidity
Data structures
Genes
Cells
Proteins
Imaging techniques
Therapeutics
Neoplasms

ASJC Scopus subject areas

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

Cite this

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

Cell-specific targeting by heterobivalent ligands. / Josan, Jatinder S.; Handl, Heather L.; Sankaranarayanan, Rajesh; Xu, Liping; Lynch, Ron; Vagner, Josef; Mash, Eugene A; Hruby, Victor J; Gillies, Robert J.

In: Bioconjugate Chemistry, Vol. 22, No. 7, 20.07.2011, p. 1270-1278.

Research output: Contribution to journalArticle

Josan, JS, Handl, HL, Sankaranarayanan, R, Xu, L, Lynch, R, Vagner, J, Mash, EA, Hruby, VJ & Gillies, RJ 2011, 'Cell-specific targeting by heterobivalent ligands', Bioconjugate Chemistry, vol. 22, no. 7, pp. 1270-1278. https://doi.org/10.1021/bc1004284
Josan JS, Handl HL, Sankaranarayanan R, Xu L, Lynch R, Vagner J et al. Cell-specific targeting by heterobivalent ligands. Bioconjugate Chemistry. 2011 Jul 20;22(7):1270-1278. https://doi.org/10.1021/bc1004284
Josan, Jatinder S. ; Handl, Heather L. ; Sankaranarayanan, Rajesh ; Xu, Liping ; Lynch, Ron ; Vagner, Josef ; Mash, Eugene A ; Hruby, Victor J ; Gillies, Robert J. / Cell-specific targeting by heterobivalent ligands. In: Bioconjugate Chemistry. 2011 ; Vol. 22, No. 7. pp. 1270-1278.
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