Combined thioether/hydrazone chemoselective ligation reactions for the synthesis of glycocluster-antigen peptide conjugates

Hydrazone/thioether ligation reactions show promise for the synthesis of clustered glycosides-antigen conjugates. Due to its propensity to aggregate, tetanus toxoid-derived epitopic peptide TT830-846 was elected to further evaluate this three-component ligation process. This difficult sequence was supplemented by a hydrazine or a glyoxylyl group either at its C- or N-terminus. The peptide-hydrazines or peptide-aldehydes thus obtained were coupled with glyoxylyl- (or hydrazino-) N-chloroacetylated-L-lysinyl trees and 2-thioethyl-alpha-D-mannopyranoside. As anticipated the ligations were controlled by the nature of the peptide and proved difficult for the C-terminal aldehyde derivative. However, when the process was performed in absence of buffer and using mannitol as a dispersing agent, all combinations finally led to the expected glycoconjugates in 40-60% purified yields.