A sucrose-derived scaffold for multimerization of bioactive peptides

Venkataramanarao Rao, Ramesh Alleti, Liping Xu, Narges K. Tafreshi, David L. Morse, Robert J. Gillies, Eugene A. Mash

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

A spherical molecular scaffold bearing eight terminal alkyne groups was synthesized in one step from sucrose. One or more copies of a tetrapeptide azide, either N3(CH2)5(C=O)-His-DPhe-Arg-Trp- NH2 (MSH4) or N3(CH2)5(C=O)-Trp-Met- Asp-Phe-NH2 (CCK4), were attached to the scaffold via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Competitive binding assays using Eu-labeled probes based on the superpotent ligands Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH2 (NDP-a-MSH) and Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe-NH2 (CCK8) were used to study the interactions of monovalent and multivalent MSH4 and CCK4 constructs with Hek293 cells engineered to overexpress MC4R and CCK2R. All of the monovalent and multivalent MSH4 constructs exhibited binding comparable to that of the parental ligand, suggesting that either the ligand spacing was inappropriate for multivalent binding, or MSH4 is too weak a binder for a second 'anchoring' binding event to occur before the monovalently-bound construct is released from the cell surface. In contrast with this behavior, monovalent CCK4 constructs were significantly less potent than the parental ligand, while multivalent CCK4 constructs were as or more potent than the parental ligand. These results are suggestive of multivalent binding, which may be due to increased residence times for monovalently bound CCK4 constructs on the cell surface relative to MSH4 constructs, the greater residence time being necessary for the establishment of multivalent binding.

Original languageEnglish (US)
Pages (from-to)6474-6482
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number21
DOIs
StatePublished - Nov 1 2011

Keywords

  • Cholecystokinin 2 receptor ligands
  • Melanocortin 4 receptor ligands
  • Multimeric ligands

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Rao, V., Alleti, R., Xu, L., Tafreshi, N. K., Morse, D. L., Gillies, R. J., & Mash, E. A. (2011). A sucrose-derived scaffold for multimerization of bioactive peptides. Bioorganic and Medicinal Chemistry, 19(21), 6474-6482. https://doi.org/10.1016/j.bmc.2011.08.053