Abstract:Reduced amide pseudopeptides have been proposed as structural probes that could be useful as potential malarial vaccine components. However, designing determined pseudopeptide sequences containing isoster peptide bonds, either on an asparagine (Asn) or on a glutamine (Gln) residues, can become difficult because these precursor amino acid aldehydes are obtained in yields lower than 0.5%. This work presents a new strategy for obtaining both Asn and Gln aldehydes based on a controlled side-chain protection approa… Show more
“…Compound ( 3 ) harboring the iminium ion is susceptible to a specific reduction with sodium cyanoborohydride (NaCNBH 3 ), to allow ( 4 ). The process has an overall 60–70 % yield represented by compound ( 5 ) when carried out with any given amino acid, except asparagine and glutamine (Asn and Gln) which need to be treated in a different way, as discussed elsewhere (Carreño et al 2011). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…We have thus recently proposed a novel strategy for obtaining both Asn and Gln aldehyde synthons based on a controlled side-chain protection approach, as well as a suitable solvent partition procedure affording yields higher than 80 % (Carreño et al 2011). The analog coded ψ-128, harboring a reduced amide bond located just between the Ile-Asn amino acid pair, represented an experimental challenge in the present work.…”
The aim of obtaining novel vaccine candidates against malaria and other transmissible diseases can be partly based on selecting non-polymorphic peptides from relevant antigens of pathogens, which have to be then precisely modified for inducing a protective immunity against the disease. Bearing in mind the high degree of the MSA-221–40 peptide primary structure’s genetic conservation among malaria species, and its crucial role in the high RBC binding ability of Plasmodium falciparum (the main agent causing malaria), structurally defined probes based on non-natural peptide-bond isosteres were thus designed. Thus, two peptide mimetics were obtained (so-called reduced amide pseudopeptides), in which naturally made amide bonds of the 30FIN32-binding motif of MSA-2 were replaced with ψ–[CH2–NH] methylene amide isostere bonds, one between the F–I and the second between I–N amino acid pairs, respectively, coded as ψ-128 ψ-130. These peptide mimetics were used to produce poly- and monoclonal antibodies in Aotus monkeys and BALB/c mice. Parent reactive mice-derived IgM isotype cell clones were induced to Ig isotype switching to IgG sub-classes by controlled in vitro immunization experiments. These mature isotype immunoglobulins revealed a novel epitope in the MSA-225–32 antigen and two polypeptides of rodent malaria species. Also, these antibodies’ functional activity against malaria was tested by in vitro assays, demonstrating high efficacy in controlling infection and evidencing neutralizing capacity for the rodent in vivo malaria infection. The neutralizing effect of antibodies induced by site-directed designed peptide mimetics on Plasmodium’s biological development make these pseudopeptides a valuable tool for future development of immunoprophylactic strategies for controlling malarial infection.
“…Compound ( 3 ) harboring the iminium ion is susceptible to a specific reduction with sodium cyanoborohydride (NaCNBH 3 ), to allow ( 4 ). The process has an overall 60–70 % yield represented by compound ( 5 ) when carried out with any given amino acid, except asparagine and glutamine (Asn and Gln) which need to be treated in a different way, as discussed elsewhere (Carreño et al 2011). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…We have thus recently proposed a novel strategy for obtaining both Asn and Gln aldehyde synthons based on a controlled side-chain protection approach, as well as a suitable solvent partition procedure affording yields higher than 80 % (Carreño et al 2011). The analog coded ψ-128, harboring a reduced amide bond located just between the Ile-Asn amino acid pair, represented an experimental challenge in the present work.…”
The aim of obtaining novel vaccine candidates against malaria and other transmissible diseases can be partly based on selecting non-polymorphic peptides from relevant antigens of pathogens, which have to be then precisely modified for inducing a protective immunity against the disease. Bearing in mind the high degree of the MSA-221–40 peptide primary structure’s genetic conservation among malaria species, and its crucial role in the high RBC binding ability of Plasmodium falciparum (the main agent causing malaria), structurally defined probes based on non-natural peptide-bond isosteres were thus designed. Thus, two peptide mimetics were obtained (so-called reduced amide pseudopeptides), in which naturally made amide bonds of the 30FIN32-binding motif of MSA-2 were replaced with ψ–[CH2–NH] methylene amide isostere bonds, one between the F–I and the second between I–N amino acid pairs, respectively, coded as ψ-128 ψ-130. These peptide mimetics were used to produce poly- and monoclonal antibodies in Aotus monkeys and BALB/c mice. Parent reactive mice-derived IgM isotype cell clones were induced to Ig isotype switching to IgG sub-classes by controlled in vitro immunization experiments. These mature isotype immunoglobulins revealed a novel epitope in the MSA-225–32 antigen and two polypeptides of rodent malaria species. Also, these antibodies’ functional activity against malaria was tested by in vitro assays, demonstrating high efficacy in controlling infection and evidencing neutralizing capacity for the rodent in vivo malaria infection. The neutralizing effect of antibodies induced by site-directed designed peptide mimetics on Plasmodium’s biological development make these pseudopeptides a valuable tool for future development of immunoprophylactic strategies for controlling malarial infection.
This protocol describes a convergent synthesis of reduced amide bond peptidomimetics using thioacid-terminated peptides and aziridine-containing peptide conjugates. This approach could be used to produce peptides and proteins with modified backbones. The peptide conjugates are made using readily available aziridine aldehydes. The convergent synthesis of peptidomimetics is demonstrated through the preparation of long and short peptide fragments with an aminomethylene group incorporated within them. This transformation is amenable to the synthesis of peptides with reduced amide bonds at cysteine and alanine. The procedure describes the preparation of each component used and highlights the ease of synthesis of aminomethylene peptidomimetics, and takes about 3 d to complete.
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