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

Abstract

As microbes use many mechanisms for avoiding immunological pressure, new strategies must be developed to bypass the immunological code of silence of conserved, functionally-important amino acid sequences, such as those involved in high activity binding peptides' (HABPs) attaching to their host cells. Hundreds of experiments in large numbers of Aotus monkeys revealed that this immunological code of silence could be broken by shifting the polarity of some critical host cell binding residues in these HABPs by substituting F for R and vice versa, Y<-->W, L<-->H, I<-->N, P<-->D, M<-->K or E, C<-->T, V<-->N or S; there are special rules for A, G and S. (1)H-nuclear magnetic resonance of these modified, immunogenic, protection-inducing HABPs and molecular modelling revealed that such modifications induced appropriate fitting into specific HLA-DRbeta1 Pockets, suggesting the presence of new pockets and a haplotype- and allele-specific conscious TCR. A highly immunogenic and protection-inducing anti-malarial vaccine can thus be produced.

Identification of the Plasmodium falciparum rhoptry neck protein 5 (PfRON5)

“…Our group has been working for more than three decades in figuring out a rational methodology for vaccine development which includes functional assays to determine those peptide regions involved in target cell binding and then performing specific modifications to them to allow a better fit into immune system molecules. This approach has allowed us to turn nonimmunogenic conserved binding regions to target cells into immunogenic and protection-inducing ones, when they are tested in the Aotus monkey model (Patarroyo et al, 2004Cifuentes et al, 2008;.…”

Protective immunity provided by a new modified SERA protein peptide: its immunogenetic characteristics and correlation with 3D structure

“…Similar results were obtained when other modifications were made, such as changing critical residues in other analogous peptides synthesised. On the contrary, immunogenicity and protection were induced in Aotus monkeys inoculated with modified HABP 23426 where changes were made to residues T7C, L14H and T16V (Table 1), categorically confirming that critical binding residues or their neighbours have to be changed for others having similar mass and volume but apposite polarity (Cifuentes et al 2008;Patarroyo et al 2008Patarroyo et al , 2011.…”

“…The recognition of protein bands agreed with proteins' theoretical weight from which their amino acid sequences or their cleavage products were derived. Molecular weight markers are shown to the left in kDa, while the molecular weights of recognised bands are shown to the right thoroughly described beforehand (Cifuentes et al 2008). This rendered some of these modified HABPs highly immunogenic, as assessed by antibodies production against the parasite or its proteins, and protection induction against challenge with a highly infectious P. falciparum strain adapted to Aotus monkeys (a primate species highly susceptible to human malaria).…”

Recent advances in the development of a chemically synthesised anti-malarial vaccine

“…This was achieved after synthesising~40,000 analogues and carrying out more than 4000 trials in the experimental monkey model, showing that critical binding residues had to be replaced by other residues having similar mass, volume and surface, but of opposite polarity; for example, F by R, W by Y, L by H, P by D, C by T, M by K, small residues like A by S (as there were no amino acids for G having opposite polarity, special consideration being taken since G acts as an a-helix breaker) [75,76].…”