Protection against malaria induced by chirally modified Plasmodium falciparum’s MSP-1 42 pseudopeptides

• Published in: Biochemical and biophysical research communications 2005-04, Vol.329 (3), p.1053-1066
• Main Authors: Lozano, José Manuel, Espejo, Fabiola, Vera, Ricardo, Vargas, Luis Eduardo, Rosas, Jaiver, Lesmes, Liliana, Torres, Elizabeth, Cortés, Jimena, Silva, Yolanda, Patarroyo, Manuel Elkin
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Animals; Antimalarials; Aotidae; Binding Sites; Cells, Cultured; Chirality; Computer Simulation; Humans; Isomerism; Malaria Vaccines; Malaria, Falciparum - immunology; Malaria, Falciparum - prevention & control; Merozoite surface protein-1; Mice; Mice, Inbred BALB C; Models, Molecular; Plasmodium falciparum - immunology; Plasmodium falciparum - metabolism; Protein Binding; Protein Conformation; Pseudopeptide; Structure-Activity Relationship; Sub-unit malarial vaccine; Subtilisins - chemistry; Subtilisins - immunology; Subtilisins - therapeutic use; Women; α-carbon asymmetry
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2005.01.165

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-[CH 2–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-[CH 2–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-1 42 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.