Modified merozoite surface protein‐1 peptides with short alpha helical regions are associated with inducing protection against malaria

Abstract

The merozoite surface protein-1 represents a prime candidate for development of a malaria vaccine. Merozoite surface protein-1 has been shown to demonstrate high-activity peptide binding to human red blood cells. One of the high-activity binding peptides, named 5501, located in the N-terminus (amino acid sequence MLNISQHQCVKKQ CPQNS) of the 19-kDa molecular mass fragment of merozoite surface protein-1, is conserved, nonimmunogenic and nonprotective. Its critical binding residues were identified and replaced with amino acids of similar mass but different charge, in order to modify their immunogenic and protective characteristics. Three analogues with positive or negative immunological results were studied by nuclear magnetic resonance to correlate their three-dimensional structure with their biological functions. The studied peptides presented a-helical fragments, but in different peptide regions and extensions, except for randomly structured 5501. We show that altering a few amino acids induced immunogenicity and protectivity against experimental malaria and changed the peptide three-dimensional structure, suggesting a better fit with immune-system molecules.

Shifting the Polarity of some Critical Residues in Malarial Peptides Binding to Host Cells is a Key Factor in Breaking Conserved Antigens Code of Silence

“…This was followed by charge modification, also being accompanied by disappointing negative results. However, some of these modified conserved HABPs were reproducibly able to induce antibody production and protective immune responses, in some monkeys, when polarity was shifted in some of these critical residues, thereby allowing us to break the conserved antigens' code of silence, as shown here and for many individual peptides thoroughly described [24][25][26][27][28][29][30][31][32].…”

“…Trying to find an association between structure and immunological performance, structural analysis by 1 H-NMR revealed striking differences between native and immunogenic protection-inducing modified HABPs [24][25][26][27][28][29][30][31][32].…”

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

“…41,44,[50][51][52][53][54][55][56][57][58] This distance was 6.5 ( 0.5 Å and 4.5 ( 1.5 Å shorter in short-lived and long-lasting antibody-inducing but non-protection-inducing modified HABPs, respectively, than in immunogenic, protection-inducing ones; residue orientation was also different. 42,43 In essence, immunogenic protection-inducing modified conserved HABPs have been modified so that they can fit perfectly into the MHC II-peptide-TCR complex for triggering an appropriate immune response, providing tremendous support for using chemically synthesized, specifically modified conserved HABPs in vaccine development.…”

Elongating modified conserved peptides eliminates their immunogenicity and protective efficacy against P. falciparum malaria

“…Numerous studies of Aotus monkeys being immunised with conserved HABPs have found that they were not immunogenic or protection-inducing since they did not induce the production of antibodies against the parasite or induce protection for these immunised monkeys against experimental challenge with a P. falciparum strain 100% infective for this specie (Bermúdez et al, 2005;Cifuentes et al, 2003a,b;Cubillos et al, 2003;Espejo et al, 2004Espejo et al, , 2001Purmova et al, 2002;Salazar et al, 2002;Torres et al, 2003).…”

“…Later studies with modified HABPs critical RBC binding residues (previously identified by scanning glycine analogues) showed that modifying some of these conserved HABPsÕ critical binding residues by amino acids having similar mass but opposite polarity made them able to become highly immunogenic and capable of inducing a protection-inducing immune response (Bermú dez et al, 2005;Cifuentes et al, 2003a,b;Cubillos et al, 2003;Espejo et al, 2004Espejo et al, , 2001Purmova et al, 2002;Salazar et al, 2002;Torres et al, 2003).…”