Orientating Peptide Residues and Increasing the Distance between Pockets to Enable Fitting into MHC−TCR Complex Determine Protection against Malaria

Abstract

The erythrocyte binding antigen EBA-175 is a 175-kDa Plasmodium falciparum protein, which has been shown to be involved in the process of invasion of erythrocytes. It has been found that conserved peptide 1818 belonging to this protein has high red blood cell binding capacity and plays an important role in the invasion process. This peptide is neither immunogenic nor protective. Peptide 1818 analogues had some of their previously recognized critical red blood cell binding residues substituted for amino acids having similar volume or mass but different polarity to make them fit into HLA-DRbeta(1)*1101 molecules; these 1818 peptide analogues were then synthesized and inoculated into Aotus nancymaae monkeys, generating different immunogenic and/or protective immune responses. Short structures such as 3(10)-helix, classical, or distorted type-III beta-turns were found in the immunogenic and protective peptides once the secondary structure had been analyzed by NMR and its structure correlated with its immunological properties. These data suggest that peptide flexibility may lead to better fitting into immune system molecules, therefore making them excellent candidates for consideration as components of a subunit-based, multicomponent synthetic antimalarial vaccine.

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

“…The other distances between their corresponding atoms and molecules were manually established. and bound with high affinity to HLA-DR 1* 0101 molecules [44], being the only one identified to date presenting such affinity) showed that, when the HA peptide was replaced by 24166 in HLA-DR 1* 0101-HA complex, it fitted well into this molecule's PBR (Fig. 4c) and five of the nine hydrogen bonds became spontaneously established (Fig.…”

“…It is worth stressing that these molecules' threedimensional structures here displayed were established by totally different methods: X-ray crystallography for HLA-DR 1* 0401, crystallised together with COL II peptide [45] and HLA-DR 1* 0101 crystallised with HA peptide (306-318) [46] whilst the three-dimensional structures of modified HABPs 24112 and 24166 were determined by 1 HNMR in solution [28,44]. It is thus not strange that slight differences could have been due to the different methodologies used for their study (crystallography cf 1 H-NMR).…”

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.…”

Functional, Immunological and Three-Dimensional Analysis of Chemically Synthesised Sporozoite Peptides as Components of a Fully-Effective Antimalarial Vaccine

“…Western blot (WB) has been used with the above antibodies for recognising molecules having a molecular weight corresponding to that from which the amino acid sequence was derived. However, more importantly, modified HABPS have also induced immune protection against experimental infection in the Aotus monkey model using the highly-infective Aotus-adapted P. falciparum FVO strain [16,71,86,87], clearly showing that chemically-synthesised, short, modified HABPs can become highly immunogenic and able to induce full protective immunity, thereby breaking the aforesaid "immunological code of silence" and establishing a Decalogue of principles or rules which have been summarised recently in an in-depth review of the field [16].…”

“…Such modifications have specifically affected their critical binding residues' polarity but have conserved the same volume and mass [5,10,14,16,71,78,84,85,87,145,158]. This feature has been closely related to conserved HABPs' 3D structure which may be specifically modified to enable modified HABPs' enhanced interaction with immune system molecules and facilitate stable Class II molecule-peptide-T-cell receptor (MHCIIpeptide-TCR) formation [106].…”