Synthesis and evaluation of bivalent NDP-α-MSH(7) peptide ligands for binding to the human melanocortin receptor 4 (hMC4R)

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

Research output: Contribution to journalArticle

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Abstract

We demonstrate the potential utility of multivalent ligands as targeting agents for cancer imaging or therapy by determining the binding of homobivalent ligands to their corresponding receptors. This manuscript details the synthesis and evaluation of a series of bivalent ligands containing two copies of the truncated heptapeptide version of [Nle4-D-Phe7]-α- melanocyte stimulating hormone (NDP-α-MSH), referred to as MSH(7). These were connected with various semirigid linkers containing Pro-Gly repeats, with or without flexible poly(ethylene glycol) (PEGO) moieties at their termini. Modeling data suggest a distance of 20-50 Å between the ligand binding sites of two adjacent G-protein coupled receptors, GPCRs. These bivalent ligands were observed to bind with higher affinity compared to their monovalent counterparts. Data suggest these ligands may be capable of cross-linking adjacent receptors. An optimal linker length of 25 ± 10 Å, inferred from these ligands, correlated well with the interreceptor distance estimated through modeling. Although there was no difference in maximal binding affinities between the ligands constructed with the Pro-Gly repeats versus those constructed with the PEGO inserts, the PEGO-containing ligands bound with high affinities over a greater range of linker lengths.

Original languageEnglish (US)
Pages (from-to)1101-1109
Number of pages9
JournalBioconjugate Chemistry
Volume18
Issue number4
DOIs
StatePublished - Jul 2007

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Melanocyte-Stimulating Hormones
Hormones
Peptides
Ligands
Ethylene Glycol
prolylglycine
Polyethylene glycols
human MC4R protein
Binding sites
G-Protein-Coupled Receptors
Data structures
Binding Sites
Proteins
Imaging techniques

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Clinical Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

Synthesis and evaluation of bivalent NDP-α-MSH(7) peptide ligands for binding to the human melanocortin receptor 4 (hMC4R). / Handl, Heather L.; Sankaranarayanan, Rajesh; Josan, Jatinder S.; Vagner, Josef; Mash, Eugene A; Gillies, Robert J.; Hruby, Victor J.

In: Bioconjugate Chemistry, Vol. 18, No. 4, 07.2007, p. 1101-1109.

Research output: Contribution to journalArticle

Handl, Heather L. ; Sankaranarayanan, Rajesh ; Josan, Jatinder S. ; Vagner, Josef ; Mash, Eugene A ; Gillies, Robert J. ; Hruby, Victor J. / Synthesis and evaluation of bivalent NDP-α-MSH(7) peptide ligands for binding to the human melanocortin receptor 4 (hMC4R). In: Bioconjugate Chemistry. 2007 ; Vol. 18, No. 4. pp. 1101-1109.
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