Squalene-derived flexible linkers for bioactive peptides

Bhumasamudram Jagadish, Rajesh Sankaranarayanan, Liping Xu, Reyniak Richards, Josef Vagner, Victor J. Hruby, Robert J. Gillies, Eugene A. Mash

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

A regiochemical and stereochemical mixture of flexible linkers bearing terminal azide functionality was synthesized in two steps from squalene and was used to connect two high affinity NDP-α-MSH ligands or two low affinity MSH(4) ligands. The ligands were N-terminally acylated using N-hydroxysuccinimidoyl 5-hexynoate and were subsequently attached to the linker via copper-catalyzed 'click' 3 + 2 cyclization of the azide and alkyne moieties. In vitro biological evaluations showed that the binding affinity to the human melanocortin 4 receptor was not diminished for most linker-ligand combinations relative to the corresponding parental ligand. Statistical and cooperative binding effects were observed for dimeric constructs containing the low affinity ligand MSH(4), but not for dimeric NDP-α-MSH constructs, presumably due to slow off rates for this high affinity ligand.

Original languageEnglish (US)
Pages (from-to)3310-3313
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume17
Issue number12
DOIs
StatePublished - Jun 15 2007

Keywords

  • Click chemistry
  • Ligands
  • Melanocyte stimulating hormone
  • Multimeric
  • NDP-α-MSH

ASJC Scopus subject areas

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

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