Protection against malaria induced by chirally modified Plasmodium falciparum's MSP-1₄₂ pseudopeptides

The C-terminal portion of the Plasmodium falciparum blood stage MSP-1 antigen plays a key role in invasion of human erythrocytes. The MSP-1 ^1282-1301 non-polymorphic 1585 peptide, from the processed MSP-1 ₄₂ fragment, is poorly immunogenic and highly α-helical [Angew. Chem. Int. Ed. 40 (2001) 4654]. Assessing the α-carbon asymmetry and its implication in the host immune response is proposed in this work to overcome the 1585 peptide's immunological properties. Accordingly, the effect of incorporating single d-amino acids and ψ-[CH₂-NH] isoster bonds into the 1585 peptide was examined both at the immunogenic and 3D-structure levels. Therefore, specific binding to RBCs is promoted by site-directed chiral modifications on the native peptide as well as by simultaneously combining specific d-substitutions with ψ-[CH₂-NH] isoster bonds transforming this molecule into a high specific HLAβ1*1101 allele binder. d-analog pseudopeptide immunized animals induced antibodies selectively recognizing a recombinant as well as native MSP-1₄₂ and MSP-1 ₃₃ fragments. Protection and low parasitemia levels were induced in Aotus monkeys immunized with the EVLYL(dK)PLAGVYRSLKKQLE analog. Peptide α-carbon chiral transformation is therefore an important target for structural modulation and, consequently, represents a novel approach towards designing multi-component subunit-based malarial vaccines.