MSP-1 Malaria Pseudopeptide Analogs: Biological and Immunological Significance and Three-Dimensional Structure

Abstract

Merozoite Surface Protein-1 (MSP-1) has been considered as a malaria vaccine candidate. It is processed during the Plasmodium falciparum invasion process of red blood cells (RBCs). A conserved MSP-1 C-terminal peptide was identified as a high-activity erythrocyte-binding peptide (HAEBP) termed 1585. Since conserved HAEBPs are neither antigenic nor immunogenic we decided to assess the significance of a single peptide bond replacement in 1585. Thus, two pseudopeptides were obtained by introducing a Y[CH2-NH] reduced amide isoster into the 1585 critical binding motif. The pseudopeptides bound to different HLA-DR alleles, suggesting that backbone modifications affect MHC-II binding patterns. Pseudopeptide-antibodies inhibit in vitro parasite RBC invasion by recognizing MSP-1. Each pseudopeptide-induced antibody shows distinct recognition patterns. 1H-NMR studies demonstrated that isoster bonds modulate the pseudopeptides' structure and thus their immunological properties, therefore representing a possible subunit malaria vaccine component.

The Next Vaccine Generation Against Malaria: Structurally Modulated Plasmodium Antigens

“…Similarly, CD profile for the L-native sequence compared with that of the Retro-inverso analogue (green line), behave as mirror images of each other bearing in mind that both were made with only l-amino acids, but having opposite peptide backbone orientation. [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] peptide. The native sequence is represented in capital letters for l-amino acids, D-enantiomer represented by lowercase letters purple highlighted, Retro-sequence is constituted by d-amino acids in lowercase letters blue highlighted and the so-named Retro-inverso peptidomimetic is confirmed by l-amino acids green highlighted.…”

“…The native sequence is represented in capital letters for l-amino acids, D-enantiomer represented by lowercase letters purple highlighted, Retro-sequence is constituted by d-amino acids in lowercase letters blue highlighted and the so-named Retro-inverso peptidomimetic is confirmed by l-amino acids green highlighted. (B) Circular dichroism secondary structure patterns for PfMSP1 [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] peptido-mimetics. Used color code was black line for the native sequence, purple for its D-enantiomer, blue line for the Retro-analogue and green line for the Retroinverso peptido-mimetic.…”

“…Used color code was black line for the native sequence, purple for its D-enantiomer, blue line for the Retro-analogue and green line for the Retroinverso peptido-mimetic. Competition ELISA was used for the PfMSP1 [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] peptide mapping with monoclonal antibodies coded Ig-αψ-437( 52 V-L 53 ) and Ig-αψ-439( 51 M-V 52 ) as shown in (C) and (D), respectively. IC50 μM values represent the average of data obtained in triplicate.…”

Recent Advances in the Synthesis and Applications of Reduced Amide Pseudopeptides

“…While peptide 1585 was poorly immunogenic, probably due to its structurally wellorganized, helical conformation, replacement of a single peptide bond by a [CH 2 NH] isostere modulated the entire three-dimensional structure of the peptide, and thus enhanced its immunogenicity. These studies demonstrated that isosteric bonds modulate the pseudopeptide structures and thus their immunological properties, thereby representing a possible subunit for a malaria vaccine component [47,48]. Reduced peptide bond analogues of an immunodominant epitope of the melanoma MART-1 protein have also been developed by Quesnel and coworkers [49], with the intention of increasing its binding to the class I HLA-A2 molecule, and ultimately enhancing its immunogenicity.…”

A New Approach to Obtaining N α‐t‐Boc‐Amino Acid Aldehydes from Asparagine and Glutamine for Reduced Amide Pseudopeptide Solid‐Phase Synthesis

“…N a -t-boc-Asn ⁄ Gln(xanthyl)-amino acid derivative molecular structure families. Compounds (1),(2) and(3) belong to N a -t-boc-Asn(Xan)-amino acid and compounds (4),(5) and(6) to N a -t-boc-Gln(Xan) amino acid.d = 7.03 p.p.m. (d, 1H, 2H, 2Hd-xanthyl, J = 6.78 Hz); d = 7.05 p.p.m.…”