Abstract |
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 alpha-helical [Angew. Chem. Int. Ed. 40 (2001) 4654]. Assessing the alpha- 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 psi-[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 psi-[CH(2)-NH] isoster bonds transforming this molecule into a high specific HLAbeta1*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 alpha- 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.
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Authors | José Manuel Lozano, Fabiola Espejo, Ricardo Vera, Luis Eduardo Vargas, Jaiver Rosas, Liliana Lesmes, Elizabeth Torres, Jimena Cortés, Yolanda Silva, Manuel Elkin Patarroyo |
Journal | Biochemical and biophysical research communications
(Biochem Biophys Res Commun)
Vol. 329
Issue 3
Pg. 1053-66
(Apr 15 2005)
ISSN: 0006-291X [Print] United States |
PMID | 15752762
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antimalarials
- Malaria Vaccines
- Subtilisins
- sub-2 protein, Plasmodium falciparum
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Topics |
- Amino Acid Substitution
- Animals
- Antimalarials
- Aotidae
- Binding Sites
- Cells, Cultured
- Computer Simulation
- Humans
- Isomerism
- Malaria Vaccines
- Malaria, Falciparum
(immunology, prevention & control)
- Mice
- Mice, Inbred BALB C
- Models, Molecular
- Plasmodium falciparum
(immunology, metabolism)
- Protein Binding
- Protein Conformation
- Structure-Activity Relationship
- Subtilisins
(chemistry, immunology, therapeutic use)
- Women
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