The Next Vaccine Generation Against Malaria: Structurally Modulated Plasmodium Antigens

Abstract

Challenges for obtaining more effective malaria vaccines depend on precise selection of antigenic motifs and understanding the complexity of Plasmodium spp. life cycle. Naturally expressed antigens are characterized for being weak immunogenic when tested as vaccine components, thus these have to be strategically modified to render them immunogenic. A molecular clue in this pursuit is provided by the chemical peptide-bond processing by peptidases, which follows a multistep pathway including ephemeral high energy molecular complexes known as transition states. Thus, we have proposed non-natural peptide-bond isosteres as transition states mimetics, and therefore, stabilizing these high-energy states with site-directed designed immunomimetics have demonstrated being a rational approach for stimulating antibody populations harboring multiple functional capacities. Therefore, peptide-bond substitutes constitute a coherent pathway towards obtaining selected immuno-active compounds from specific plasmodial molecular objectives. Chemical strategies for synthesizing peptido-mimetics and antimalarial selected trials lead us to assess a number of peptide-bond substitutes for obtaining immuno-active and structurally defined molecules. Plasmodium antigens expressed on merozoite, sporozoite and gametocyte stages have been selected as targets and subsequently modified based on the presence of either a high-binding motif or a potential HLA-reading frame. This new family of immuno-mimetics is and efficient neutralizing antibody inducers when tested in in vitro and in vivo experiments, thus representing a new generation of malaria vaccine components.