1H-NMR structures of the Plasmodium falciparum 1758 erythrocyte binding peptide analogues and protection against malaria

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

“…This involved immunising Aotus monkeys with polymeric HABPs and challenging them with freshly obtained RBC infected with the highly infectious Aotus-adapted P. falciparum FVO strain. The results showed that, unlike HABPs having variable amino acid sequences (vHABPs) and inducing immune response, conserved HABPs (cHABPs) were poorly or nonimmunogenic (no antibodies or cellular immune responses were induced against monomer peptide, the recombinant protein and/or the native protein in the parasite as recognised by IFA) and non-protection inducing in the Aotus monkey model [67][68][69]. Our results agreed with other studies showing that proteins having variable amino acid sequences or repeats are highly antigenic and highly immunogenic but that induced immune responses are strain specific and are only protective against that specific strain [12, 70,71].…”

“…Findings by other groups have shown that replacing residues in protein or peptide sequences changed their immunological properties (reducing, suppressing or increasing them) [73], HABP analogues (glycine scanning) were then synthesised for identifying residues which were critical to HABP binding to RBC [52,67,68]. Many of these modified HABPs (mHABPs) did not induce any immune response or induce any protection after experimental challenge when tested in Aotus monkeys, whereas others were able to induce high short-lived antibody titres and others high long-lived antibody titres (unfortunately, without inducing protection) [67,68,74].…”

“…Many of these modified HABPs (mHABPs) did not induce any immune response or induce any protection after experimental challenge when tested in Aotus monkeys, whereas others were able to induce high short-lived antibody titres and others high long-lived antibody titres (unfortunately, without inducing protection) [67,68,74].…”

“…1 H-NMR (600 mHz) was used for determining and analysing more than 300 20-mer long cHABP (non-immunogenic) and mHABP (protection-inducing) 3D structures [67,68,74,78]. Recognising their binding motifs and binding registers in their amino acid sequences, together with data from molecular docking and Aotus immunisation studies led to the observation that the 3D structure of functionally relevant, native HABPs involved in the invasion of target cells were almost identical to those they displayed in recombinant protein structure determined by x-ray crystallography (regardless of the methodology used for determining them) [79].…”

“…Functional--structural analysis spanning the last 17 years has revealed that the escape mechanism had a structural basis; cHABPs had compact a-helical regions, b-sheets, b-turns or were randomly structured, but those having short or a-helix regions, type I b-turns or 3 10 distorted a-helix structures were most easily modified to render them highly immunogenic and able to induce a full protection-inducing immune response, which was strongly associated with polyproline type II left-handed-like (PPII L ) structures [67,68,74,[83][84][85][86][87][88].…”