A solanesol-derived scaffold for multimerization of bioactive peptides

Ramesh Alleti, Venkataramanarao Rao, Liping Xu, Robert J. Gillies, Eugene A Mash

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

A flexible molecular scaffold bearing varying numbers of terminal alkyne groups was synthesized in five steps from solanesol. R(CO)-MSH(4)-NH2 ligands, which have a relatively low affinity for binding at the human melanocortin 4 receptor (hMC4R), were prepared by solid phase synthesis and were N-terminally acylated with 6-azidohexanoic acid. Multiple copies of the azide N3(CH2)5(CO)-MSH(4)-NH2 were attached to the alkyne-bearing, solanesol-derived molecular scaffold via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Control studies showed that the binding affinity of the triazole-containing ligand, CH 3(CH2)3(C2N3)(CH 2)5(CO)-MSH(4)-NH2, was not significantly diminished relative to the corresponding parental ligand, CH3(CO)- MSH(4)-NH2. In a competitive binding assay with a Eu-labeled probe based on the superpotent ligand NDP-α-MSH, the monovalent and multivalent constructs appear to bind to hMC4R as monovalent species. In a similar assay with a Eu-labeled probe based on MSH(4), modest increases in binding potency with increased MSH(4) content per scaffold were observed.

Original languageEnglish (US)
Pages (from-to)5895-5903
Number of pages9
JournalJournal of Organic Chemistry
Volume75
Issue number17
DOIs
StatePublished - Sep 3 2010

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Melanocyte-Stimulating Hormones
Scaffolds
Carbon Monoxide
Peptides
Alkynes
Bearings (structural)
Ligands
Azides
Assays
Triazoles
Cycloaddition
solanesol
Copper
Acids

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

A solanesol-derived scaffold for multimerization of bioactive peptides. / Alleti, Ramesh; Rao, Venkataramanarao; Xu, Liping; Gillies, Robert J.; Mash, Eugene A.

In: Journal of Organic Chemistry, Vol. 75, No. 17, 03.09.2010, p. 5895-5903.

Research output: Contribution to journalArticle

Alleti, Ramesh ; Rao, Venkataramanarao ; Xu, Liping ; Gillies, Robert J. ; Mash, Eugene A. / A solanesol-derived scaffold for multimerization of bioactive peptides. In: Journal of Organic Chemistry. 2010 ; Vol. 75, No. 17. pp. 5895-5903.
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