Synthesis and bioactivity of MSH4 oligomers prepared by an A<inf>2</inf> + B<inf>2</inf> strategy

Dilani Chathurika Dehigaspitiya, Suryakiran Navath, Craig S. Weber, Ron Lynch, Eugene A Mash

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Abstract Oligomers incorporating the tetrapeptide MSH4, the minimum active sequence of melanocyte stimulating hormone, were synthesized by an A<inf>2</inf> + B<inf>2</inf> strategy involving microwave-assisted copper-catalyzed azide-alkyne cycloaddition. A<inf>2</inf> contained an MSH4 core while B<inf>2</inf> contained a (Pro-Gly)<inf>3</inf> spacer. Soluble mixtures containing compounds with up to eight MSH4 units were obtained from oligomerizations at high monomer concentrations. The avidities of several oligomeric mixtures were evaluated by means of a competitive binding assay using HEK293 cells engineered to overexpress the melanocortin 4 receptor. When based on total MSH4 concentrations, avidities were only minimally enhanced compared with a monovalent control. The lack of variation in the effect of ligands on probe binding is consistent with high off rates for MSH4 in both monovalent and oligomeric constructs relative to that of the competing probe.

Original languageEnglish (US)
Article number45546
Pages (from-to)3060-3065
Number of pages6
JournalTetrahedron Letters
Volume56
Issue number23
DOIs
StatePublished - Jul 3 2015

Fingerprint

Bioactivity
Oligomers
varespladib methyl
prolylglycine
Receptor, Melanocortin, Type 4
Melanocyte-Stimulating Hormones
Oligomerization
Competitive Binding
Alkynes
Azides
Cycloaddition
HEK293 Cells
Cycloaddition Reaction
Microwaves
Copper
Assays
Monomers
Ligands

Keywords

  • Competitive binding assay
  • Melanocortin 4 receptor
  • Multivalent ligand
  • Oligomerization
  • Time-resolved fluorescence

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Drug Discovery

Cite this

Synthesis and bioactivity of MSH4 oligomers prepared by an A<inf>2</inf> + B<inf>2</inf> strategy. / Dehigaspitiya, Dilani Chathurika; Navath, Suryakiran; Weber, Craig S.; Lynch, Ron; Mash, Eugene A.

In: Tetrahedron Letters, Vol. 56, No. 23, 45546, 03.07.2015, p. 3060-3065.

Research output: Contribution to journalArticle

Dehigaspitiya, Dilani Chathurika ; Navath, Suryakiran ; Weber, Craig S. ; Lynch, Ron ; Mash, Eugene A. / Synthesis and bioactivity of MSH4 oligomers prepared by an A<inf>2</inf> + B<inf>2</inf> strategy. In: Tetrahedron Letters. 2015 ; Vol. 56, No. 23. pp. 3060-3065.
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AB - Abstract Oligomers incorporating the tetrapeptide MSH4, the minimum active sequence of melanocyte stimulating hormone, were synthesized by an A2 + B2 strategy involving microwave-assisted copper-catalyzed azide-alkyne cycloaddition. A2 contained an MSH4 core while B2 contained a (Pro-Gly)3 spacer. Soluble mixtures containing compounds with up to eight MSH4 units were obtained from oligomerizations at high monomer concentrations. The avidities of several oligomeric mixtures were evaluated by means of a competitive binding assay using HEK293 cells engineered to overexpress the melanocortin 4 receptor. When based on total MSH4 concentrations, avidities were only minimally enhanced compared with a monovalent control. The lack of variation in the effect of ligands on probe binding is consistent with high off rates for MSH4 in both monovalent and oligomeric constructs relative to that of the competing probe.

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