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

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.
AuthorsJosé Manuel Lozano, Fabiola Espejo, Ricardo Vera, Luis Eduardo Vargas, Jaiver Rosas, Liliana Lesmes, Elizabeth Torres, Jimena Cortés, Yolanda Silva, Manuel Elkin Patarroyo
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 329 Issue 3 Pg. 1053-66 (Apr 15 2005) ISSN: 0006-291X [Print] United States
PMID15752762 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimalarials
  • Malaria Vaccines
  • Subtilisins
  • sub-2 protein, Plasmodium falciparum
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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