Development of Designed Site-Directed Pseudopeptide-Peptido-Mimetic Immunogens as Novel Minimal Subunit-Vaccine Candidates for Malaria

Abstract

Synthetic vaccines constitute the most promising tools for controlling and preventing infectious diseases. When synthetic immunogens are designed from the pathogen native sequences, these are normally poorly immunogenic and do not induce protection, as demonstrated in our research. After attempting many synthetic strategies for improving the immunogenicity properties of these sequences, the approach consisting of identifying high binding motifs present in those, and then performing specific changes on amino-acids belonging to such motifs, has proven to be a workable strategy. In addition, other strategies consisting of chemically introducing non-natural constraints to the backbone topology of the molecule and modifying the α-carbon asymmetry are becoming valuable tools to be considered in this pursuit. Non-natural structural constraints to the peptide backbone can be achieved by introducing peptide bond isosters such as reduced amides, partially retro or retro-inverso modifications or even including urea motifs. The second can be obtained by strategically replacing L-amino-acids with their enantiomeric forms for obtaining both structurally site-directed designed immunogens as potential vaccine candidates and their Ig structural molecular images, both having immuno-therapeutic effects for preventing and controlling malaria.

Computational Studies on Structural, Excitation, and Charge-Transfer Properties of Ureidopeptidomimetics

“…The ureido group holds an amide unit with a peptide bond, which can replace the same in natural proteins. 43 With its lone pair of electrons present above and below the molecular plane, urea is found to behave as a donor or acceptor, depending on the groups to which it is attached in its CT complexes and clusters. 44,45 Urea is also a known example of a hydrogen-bond donor and acceptor and thus is used in molecular self-assembly.…”

Conserved Binding Regions Provide the Clue for Peptide-Based Vaccine Development: A Chemical Perspective

“…H-bonds’ essential role in protein structure and in immune responses has become evident, since T-cell epitopes’ total retro-inversion ( d -aa) has been seen to have very low MHC binding capability and this was non-immunogenic [ 223 ]. We have found that specifically replacing l -aa with d -aa in MSP-1-derived HABP 1513 binding motif did not reduce its binding activity, although its secondary structure became distorted, and that d -analogues were less suitable for T-cell stimulation [ 224 , 225 , 226 ]. By contrast, some d -aa replacements (one at a time) in MSP-1-derived HABP 1585 produce d -analogues having improved resistance against proteolytic degradation and higher binding activity than that the cognate peptide.…”

Peptide and protein mimetics by retro and retroinverso analogs

“…Peptides for disruption of protein-protein interaction involved in pathogenesis can be designed based on sequence fragment involved in this protein-protein interaction (Beck, 2001;Nieddu et al, 2005;Wójcik & Berlicki, 2016). But mimetics using a retroinverso analog of this inhibitor peptide will have an additional advantage that it cannot be degraded by proteases in the body (Lozano, Lesmes, Carreño, Gallego, & Patarroyo, 2010). The proteases in cells generally recognize a specific amino acid sequence made up of L amino acids; therefore, peptide drug inhibitors made up of D amino acids will not be proteolyzed by natural proteases and consequently will have a long-lasting therapeutic effect (Keil, 2012).…”