Synthetic approaches to multivalent lipopeptide dendrimers containing cyclic disulfide epitopes of foot-and-mouth disease virus

Bioconjug Chem. 2003 Jan-Feb;14(1):144-52. doi: 10.1021/bc025577f.

Abstract

The synthesis of a multiantigenic peptide dendrimer incorporating four copies of a cyclic disulfide epitope has been undertaken. Since standard chemoselective ligation procedures involving thioether formation are inadvisable in the presence of a preformed disulfide, conjugation through a peptide bond between the lipidated branched lysine scaffold and a suitably protected version of the cyclic disulfide has been used instead. Several synthetic approaches to the partially protected cyclic disulfide peptide have been explored. The most effective involves building a minimally protected version of the peptide by Boc solid phase synthesis, using fluorenyl-based anchorings and cysteine protecting groups. Peptide-resin cleavage and cysteine deprotection/oxidation are performed simultaneously by base-promoted elimination. The cyclic disulfide epitope is readily obtained in sufficient amounts by this procedure and subsequently incorporated to the lipidated lysine core by peptide bond formation in solution. A final acid deprotection step in anhydrous HF yields a peptide construction containing a maximum of three copies of the cyclic disulfide epitope, the lower substitution being attributable to steric constraints. This immunogen has been successfully used in an experimental vaccination trial against foot-and-mouth disease virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation / drug effects
  • Antigens, Viral / chemistry
  • Antigens, Viral / therapeutic use
  • Chromatography, High Pressure Liquid
  • Disulfides
  • Epitopes / chemistry*
  • Epitopes / therapeutic use
  • Foot-and-Mouth Disease Virus / immunology*
  • Guinea Pigs
  • Immunization
  • Lipoproteins / chemical synthesis*
  • Lipoproteins / immunology
  • Lipoproteins / therapeutic use
  • Peptides / chemical synthesis*
  • Peptides / immunology
  • Peptides / therapeutic use
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Vaccines / chemical synthesis

Substances

  • Antigens, Viral
  • Disulfides
  • Epitopes
  • Lipoproteins
  • Peptides
  • Vaccines