Influence of polar support for the synthesis of large C-terminal peptide aldehyde: application to chemoselective ligation

Abstract

Efficient conditions have been developed for the synthesis of large peptide aldehydes from solid support through nucleophilic displacement. Aminolysis of the ester bond between a deprotected peptide and the phenylacetamidomethyl linker with aminoacetaldehyde-dimethylacetal leads to a peptide aldehyde masked as an acetal. Besides the optimization of parameters such as solvents, workup procedure and temperature, the influence of the nature of the polymeric support was crucial. Among the solid supports tested, the poly(ethylene glycol)-poly(acrylamide) resin proved to afford the best cleavage yield. This work underlines that the solid support has to be considered as a co-solvent rather than an inert carrier. Our methodology was further applied to the synthesis of a 33-mer with T-helper activity from the fusion protein of measles virus. The 33-mer peptide aldehyde was then chemoselectively ligated via an oxime bond to an (aminooxy) acetyl peptide with T-cytotoxic activity.