Squalene-derived flexible linkers for bioactive peptides

Bioorg Med Chem Lett. 2007 Jun 15;17(12):3310-3. doi: 10.1016/j.bmcl.2007.04.001. Epub 2007 Apr 6.

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-alpha-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-alpha-MSH constructs, presumably due to slow off rates for this high affinity ligand.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alkynes / chemistry
  • Amino Acid Sequence
  • Azides / chemistry
  • Binding Sites
  • Catalysis
  • Chromatography, High Pressure Liquid
  • Copper / chemistry
  • Cyclization
  • Dimerization
  • Humans
  • Ligands
  • Mass Spectrometry
  • Molecular Sequence Data
  • Peptides / chemical synthesis
  • Peptides / pharmacology*
  • Receptor, Melanocortin, Type 4 / drug effects*
  • Receptor, Melanocortin, Type 4 / metabolism
  • Squalene / analogs & derivatives*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Succinimides / chemistry
  • alpha-MSH / analogs & derivatives
  • alpha-MSH / metabolism

Substances

  • Alkynes
  • Azides
  • Ligands
  • Peptides
  • Receptor, Melanocortin, Type 4
  • Succinimides
  • alpha-MSH
  • N-hydroxysuccinimide suberic acid ester
  • Copper
  • Squalene