Applications of Protein Epitope Mimetics in Vaccine Design.

A New Supersecondary Structure in the Circumsporozoite Protein of Plasmodium falciparum?

Abstract

An approach to synthetic vaccine design is illustrated, focusing on the immunodominant (NPNA)_n repeat region of the circumsporozoite (CS) protein of the malaria parasite Plasmodium falciparum. Modelling suggests that the NPNAN motif may adopt a helical β-turn, which is tandemly repeated in the CS protein to generate a novel supersecondary structure. Cyclic peptidomimetics of this NPNAN motif were synthesized and shown by NMR to adopt helical turns in aqueous solution. When incorporated into Immunopotentiating Reconstituted Influenza Virosomes (IRIVs), humoral immune responses were generated in mice that crossreact with native CS protein on sporozoites. IRIVs are a human-compatible delivery system that appear generally suitable for inducing antibody responses against conformational epitopes using constrained peptidomimetics. This approach may offer great potential for the design of molecularly defined synthetic vaccines, including those targeted against multiple antigens and development stages of P. falciparum, or against other infectious agents.