Distorting Malaria Peptide Backbone Structure to Enable Fitting into MHC Class II Molecules Renders Modified Peptides Immunogenic and Protective

Cifuentes, Gladys; Patarroyo, Manuel E.; Urquiza, Mauricio; Ramı́rez, Luı́s Eduardo; Reyes, Claudia; Rodríguez, Ricaurte

doi:10.1021/jm020440w

Cited by 27 publications

(69 citation statements)

References 21 publications

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“…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.…”

Section: Structural and Binding Characteristics Of Hla-dr Moleculesmentioning

confidence: 90%

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

2008

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S eventeen million people die of transmittable diseases and 2/3 of the world's population suffer them annually. Malaria, tuberculosis, AIDS, hepatitis, and reemerging and new diseases are a great threat to humankind. A logical and rational approach for vaccine development is thus desperately needed.Protein chemistry provides the best tools for tackling these problems. The tremendous complexity of microbes, the different pathways they use for invading host cells, and the immune responses they induce can only be resolved by using the minimum subunit-based (chemically produced ∼20-mer peptides), multiantigenic (most proteins involved in invasion), multistage (different invasion mechanisms) vaccine development approach.The most lethal form of malaria caused by Plasmodium falciparum (killing 3 million and affecting 500 million people worldwide annually) was used as target disease since many of its proteins, its invasion pathways, and its genome have been described recently. A New World primate (the Aotus monkey) is highly susceptibly to human malaria; its immune system molecules are 80 -100% identical to those of its human counterpart, making it an excellent model for vaccine development.Chemically synthesized ∼20-mer peptides, covering all the P. falciparum malaria proteins involved in red blood cell (RBC) invasion were synthesized by the classical t-Boc technology (based on synthetic SPf66 antimalarial vaccine information for identifying targets) and assayed in a highly sensitive, specific, and robust test for detecting receptor-ligand interactions between high-activity binding peptides (HABPs) and RBCs. HABPs were identified, some in which the molecule displays genetic variability (to be discarded due to their tremendous complexity) and elicits a strain-specific immune response and others that are conserved (no amino acid sequence variation).Conserved HABPs were synthesized in a polymeric form by adding cysteines at their N-and C-terminal ends to be used for monkey immunization. They became nonimmunogenic (no antibodies were induced) nonprotection inducers (monkeys were not protected against P. falciparum malaria challenge with a highly infective strain) suggesting a code of immunological silence or nonresponsiveness for these conserved HABPs.A large number of monkey trials involving a considerable number of Aotus monkeys were performed to break this code of immunological silence by replacing critical residues (determined by glycine peptide analogue scanning) to find that the following amino acid changes had to be made to render them antibody and protection inducing: FTR; WTY; LTH; ITN; MTK; PTD; QTE; CTT.The three-dimensional (3D) structure of >100 of these native modified HABPs (determined by 1 H NMR) revealed that the following structural changes had all to be achieved to allow a better fit into the major histocompatibility complex class II (MHC II)-peptide-TCR complex to properly activate the immune system: R-helix shortening, modifying their -turn, adopting segmental R-helix configuration, changing residue or...

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Section: Structural and Binding Characteristics Of Hla-dr Moleculesmentioning

confidence: 90%

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

2008

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“…When these polymerised conserved HABPs were used for immunisation studies in Aotus monkeys it was found that these native HABP sequences were neither immunogenic nor protection-inducing [101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116].…”

Section: Molecular Approach To the Invasion Processmentioning

confidence: 99%

“…However, whereas some HABPs modifications elicited non-protection inducing antibodies in vaccinated Aotus monkeys, [(some induced antibodies having a very short half-life) [119]], other modifications made to HABPs were able to induce high antibody titres against parasite native protein and protected Aotus monkeys from challenge with the highly infective P. falciparum FVO strain [101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116]. Although the protection levels achieved by each of these modified HABPs has been limited (Table 1), and individually slightly lower than SPf66, the purpose of our Institute it is to develop a rational methodology for obtaining multi-antigenic, multi-stage, subunit-based synthetic vaccines, malaria being one of them.…”

Section: Molecular Approach To the Invasion Processmentioning

confidence: 99%

“…Extensive 1 H-NMR studies aimed at finding an association or correlation between immunological function and 3D structure have shown that native HABPs have one of the following: a very compact α-helical structure, a totally random structure or a β-turn configuration [101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116]. These findings could partly explain their complete lack of immunogenicity and protection-inducing ability, since very compact α-helices or totally random structures or β-turns may not fit appropriately into the MHC class-II molecule groove, hampering MHCII-peptide-TCR Complex formation and impeding immune system activation.…”

Section: Molecular Approach To the Invasion Processmentioning

confidence: 99%

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Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides

Patarroyo

Cifuentes

Salazar

et al. 2005

CMC

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An anti-malarial vaccine is urgently needed, especially against P. falciparum which causes 2 to 3 million deaths each year, mostly in Sub-Saharan African children. This vaccine should contain molecules from the parasite's different developmental stages due to the parasite's remarkable complexity and genetic variability. The first approach using synthetic peptides from different parasite stage molecules (the SPf66 malaria vaccine) conferred limited protective efficacy in Aotus monkeys and in large field-trials carried out in different parts of the world SPf66 contains red blood cell (RBC) binding merozoite peptides for which immune responses against them are genetically controlled by HLA-DR region. Therefore, a systematic search of conserved high activity binding peptides (HABP) was undertaken aimed at using them as immunogens. However, these peptides were poorly immunogenic and had poor protection-inducing capacity against experimental challenge with a P. falciparum strain highly infective for Aotus monkeys an experimental model with an immune system quite similar to humans. Modifications were thus made to key residues to render them immunogenic and protection-inducing. These native and modified HABPs' three-dimensional structure was determined by (1)H-NMR studies and their ability in forming stable Major Histocompatibility Class II - peptide (MHCII-peptide) complexes was correlated with their ability to bind in vitro to purified HLA-DR beta1* molecules. Our experimental data suggests a correlation between modified HABPs' three-dimensional structure, HLA-DR beta1* binding preferences and their protection-inducing capacity in monkeys. Furthermore, the data presented here indicates that a synthetic peptide vaccine's three-dimensional structural features dictate both HLA-DR beta1* allele binding preference (imposing genetic restriction on the immune response) and on these vaccines' protection-inducing value. Basic knowledge of a parasite's functionally active peptides, their 3D structure and their interaction for forming the MHC II- peptide-TCR complex will thus contribute towards designing fully effective multi-component, multi-stage subunit-based malarial vaccines.

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“…Such modifications included displacing or shortening native molecule a-helix (Cifuentes et al, 2003b;Cubillos et al, 2003;Espejo et al, 2004;Espejo et al, 2001) or a-helicoid fragment appearing in those native HABPs having a random structure Bermú dez et al, 2005;Bermú dez et al, 2003) or b-turn III distortions (Cifuentes et al, 2003a;Purmova et al, 2002), thus stimulating a considerably improved immune response, increasing antibody titres and inducing protection in some Aotus monkeys against experimental challenge. Table 2 shows Aotus immunisation studies with their respective antibody titres against the parasite (determined by IFA) and their protection capacity regarding experimental challenge.…”

Section: Modified Habpsmentioning

confidence: 99%

Elongating modified conserved peptides eliminates their immunogenicity and protective efficacy against P. falciparum malaria

Espejo

Bermúdez

Vanegas

et al. 2005

Journal of Structural Biology

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Distorting Malaria Peptide Backbone Structure to Enable Fitting into MHC Class II Molecules Renders Modified Peptides Immunogenic and Protective

Cited by 27 publications

References 21 publications

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides

Elongating modified conserved peptides eliminates their immunogenicity and protective efficacy against P. falciparum malaria

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Distorting Malaria Peptide Backbone Structure to Enable Fitting into MHC Class II Molecules Renders Modified Peptides Immunogenic and Protective

Cited by 27 publications

References 21 publications

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

Based on HLA-DR&#946;1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides

Elongating modified conserved peptides eliminates their immunogenicity and protective efficacy against P. falciparum malaria

Contact Info

Product

Resources

About

Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides