Protection against malaria induced by chirally modified Plasmodium falciparum's MSP-1 42 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 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.
Lozano
José Manuel
JM
Fundación Instituto de Inmunología de Colombia (FIDIC), Bogotá D.C., Colombia. jm_lozano@fidic.org.co
Espejo
Fabiola
F
Vera
Ricardo
R
Vargas
Luis Eduardo
LE
Rosas
Jaiver
J
Lesmes
Liliana
L
Torres
Elizabeth
E
Cortés
Jimena
J
Silva
Yolanda
Y
Patarroyo
Manuel Elkin
ME
D019943:Amino Acid Substitution; D000818:Animals; D000962:Antimalarials; D016645:Aotidae; D001665:Binding Sites; D002478:Cells, Cultured; D003198:Computer Simulation; D006801:Humans; D007536:Isomerism; D017780:Malaria Vaccines; D016778:Malaria, Falciparum / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013381:Subtilisins / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use*; D014930:Women
D000962:Antimalarials; D017780:Malaria Vaccines; D013381:Subtilisins; C119550:sub-2 protein, Plasmodium falciparum