Synthetic approaches to multivalent lipopeptide dendrimers containing cyclic disulfide epitopes of foot-and-mouth disease virus.
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.
De Oliveira
Eliandre
E
Department of Organic Chemistry, University of Barcelona, Barcelona, Spain.
Villén
Judit
J
Giralt
Ernest
E
Andreu
David
D
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D000956:Antigens, Viral / Q000737:chemistry / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D004220:Disulfides; D000939:Epitopes / Q000737:chemistry* / Q000627:therapeutic use; D029544:Foot-and-Mouth Disease Virus / Q000276:immunology*; D006168:Guinea Pigs; D007114:Immunization; D008074:Lipoproteins / Q000138:chemical synthesis* / Q000276:immunology / Q000627:therapeutic use; D010455:Peptides / Q000138:chemical synthesis* / Q000276:immunology / Q000627:therapeutic use; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014612:Vaccines / Q000138:chemical synthesis
D000956:Antigens, Viral; D004220:Disulfides; D000939:Epitopes; D008074:Lipoproteins; D010455:Peptides; D014612:Vaccines