Probing the Linker Design of a Conjugate Peptide Vaccine

This thesis investigates different chemical approaches to facilitate the exploration of structure-activity relationships related to lipopeptide vaccine CI258, with the overall aim of improving vaccine efficacy and synthetic tractability. The vaccine design comprises a lipid antigen, which functions as a vaccine adjuvant, connected to a peptide antigen via a cleavable and self-immolative linker. In vivo processing of CI258 releases the active vaccine components, with the first step in this processing the enzymatic cleavage at the indicated site. This thesis aims to synthesise compounds that give insight into how the enzymatic cleavage rate affects activity. Topics include the synthesis of advanced  diastereomeric intermediates to probe the effect of the dipeptide linker stereochemistry. Consideration will also be given to the necessity of the immolative para-amino benzyl carbamate linker. Research towards altering the biodistribution of the vaccine design is also reported.