Modifying RESA protein peptide 6671 to fit into HLA-DRβ1* pockets induces protection against malaria

Alba, Martha Patricia; Salazar, Luz Mary; Vargas, Luis Eduardo; Trujillo, Marcelo López; López, Yolanda; Patarroyo, Manuel E.

doi:10.1016/j.bbrc.2004.02.009

Cited by 22 publications

(33 citation statements)

References 30 publications

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“…Remarkably, it was found that both Mrz-and Spz-derived mHABPs bound to different HLA-DRb1* molecules while most unmodified cHABPs did not do so or were highly promiscuous, confirming what had been postulated: the changes allowed a better fit of mHABPs into the HLA-DRb1* peptide binding region (PBR) groove and improved MHC II--mHABP interaction specificity which, in turn, was correlated with protective immunity in Aotus monkeys [76,84,89,90].…”

Section: Mhabp Structure--function Relationshipsupporting

confidence: 55%

“…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].…”

Section: Mhabp Structure--function Relationshipmentioning

confidence: 99%

“…Much of the recent body of our work has dealt with the immunogenicity (IFA and WB assays) of individual Mrz-and Spz-derived mHABPs and their protection-inducing ability by the most stringent test available (intravenous inoculation of a highly virulent Aotus-adapted P. falciparum strain), showing that mHABPs from Mrz and Spz parasite stages cover most MHC II genetic variants and face the parasite regarding two lines of defence: Spz and Mrz invasion [11,67,68,74,76,78,84,89,90].…”

Section: Components For a New Antimalarial Vaccinementioning

confidence: 99%

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

Curtidor

Patarroyo

2015

Expert Opinion on Biological Therapy

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The functional approach taken to develop a fully protective, minimal subunit-based, multiantigenic, multistage and synthetic peptide-based antimalarial vaccine has shown promising results. The clear relationship observed between mHABPs structure and their immunological properties highlights the challenges and opportunities arising from this methodology, as well as the universal principles and rules derived therefrom.

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Section: Mhabp Structure--function Relationshipsupporting

confidence: 55%

Section: Mhabp Structure--function Relationshipmentioning

confidence: 99%

Section: Components For a New Antimalarial Vaccinementioning

confidence: 99%

See 1 more Smart Citation

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

Curtidor

Patarroyo

2015

Expert Opinion on Biological Therapy

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“…The phenomenon's fine-tuning, following hundreds of experiments performed on large numbers of Aotus monkeys [81][82][83][84][85][86][87][88][89][90][91] ( Table 1), has allowed us to ascertain that some critical binding residues have to be replaced by others by specifically and reciprocally shifting their polarity but maintaining their other physicochemical characteristics, such as mass, volume and surface. F could thus be replaced by R and vice versa; L↔H, P↔D, W↔Y, M↔K and E, I↔N, T↔C and V↔N or S. Serine, alanine and glycine remained undefined owing to their very small mass, similar polarity, small volume and the absence of counterparts of opposite polarity as occurs with other amino acids.…”

Section: ) Are Usually Poor Immunogens This Has Been Found In a Largmentioning

confidence: 99%

Strategies for developing multi‐epitope, subunit‐based, chemically synthesized anti‐malarial vaccines

Patarroyo

Cifuentes

Bermúdez

et al. 2008

J Cellular Molecular Medi

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An anti-malarial vaccine against the extremely lethal Plasmodium falciparum is desperately needed. Peptides from this parasite's proteins involved in invasion and having high red blood cell-binding ability were identified; these conserved peptides were not immun genic or protection-inducing when used for immunizing Aotus monkeys. Modifying some critical binding residues in these high-activi binding peptides' (HABPs') attachment to red blood cells (RBC) allowed them to induce immunogenicity and protection against expermental challenge and acquire the ability to bind to specific HLA-DRp1* alleles. These modified HABPs adopted certain characterist structural configurations as determined by circular dichroism (CD) and 1H nuclear magnetic resonance (NMR) associated with certain HLA-DRβ1* haplotype binding activities and characteristics, such as a 2-Å-distance difference between amino acids fitting into HLA-DRp1 Pockets 1 to 9, residues participating in binding to HLA-DR pockets and residues making contact with the TCR, suggesting haplotyp and allele-conscious TCR. This has been demonstrated in HLA-DR-like genotyped monkeys and provides the basis for designing high effective, subunit-based, multi-antigen, multi-stage, synthetic vaccines, for immediate human use, malaria being one of them.

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“…Western blot (WB) has been used with the above antibodies for recognising molecules having a molecular weight corresponding to that from which the amino acid sequence was derived. However, more importantly, modified HABPS have also induced immune protection against experimental infection in the Aotus monkey model using the highly-infective Aotus-adapted P. falciparum FVO strain [16,71,86,87], clearly showing that chemically-synthesised, short, modified HABPs can become highly immunogenic and able to induce full protective immunity, thereby breaking the aforesaid "immunological code of silence" and establishing a Decalogue of principles or rules which have been summarised recently in an in-depth review of the field [16].…”

Section: Recognising and Characterising Protein Binding Sequences: Idmentioning

confidence: 99%

Functional, Immunological and Three-Dimensional Analysis of Chemically Synthesised Sporozoite Peptides as Components of a Fully-Effective Antimalarial Vaccine

Curtidor¹,

Vanegas

Alba

et al. 2011

CMC

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Our ongoing search for a fully-effective vaccine against the Plasmodium falciparum parasite (causing the most lethal form of human malaria) has been focused on identifying and characterising proteins' amino acid sequences (high activity binding peptides or HABPs) involved in parasite invasion of red blood cells (RBC) by the merozoite and hepatocytes by the sporozoite. Many such merozoite HABPs have been recognised and molecularly and structurally characterised; however, native HABPs are immunologically silent since they do not induce any immune response or protection against P. falciparum malaria infection and they have to be structurally modified to allow them to fit perfectly into immune system molecules. A deeply structural analysis of these conserved merozoite HABPs and their modified analogues has led to rules or principles becoming recognised for constructing a logical and rational methodology for a minimal subunit-based, multi-epitope, multi-stage, chemically-synthesised vaccine. The same in-depth analysis of the most relevant sporozoite proteins involved in sporozoite cell-traversal and hepatocyte invasion as well as the hepatic stage is shown here. Specifically modifying these HABPs has resulted in a new set of potential pre-erythrocyte targets which are able to induce high, longlasting antibody titres in Aotus monkeys, against their corresponding recombinant proteins and the complete parasite native molecules. This review shows how these rules may be applied against the first stage of parasite invasion (i.e. the sporozoite) to mount the first line of defence against the malarial parasite, which may indeed be the most effective one. Our results strongly support including some of these modified sporozoite HABPs in combination with the previously-described modified merozoite HABPs for obtaining the aforementioned fully-protective, multiepitope, multi-stage, minimal subunit-based, chemically-synthesized, antimalarial vaccine.

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Modifying RESA protein peptide 6671 to fit into HLA-DRβ1* pockets induces protection against malaria

Cited by 22 publications

References 30 publications

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

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

Strategies for developing multi‐epitope, subunit‐based, chemically synthesized anti‐malarial vaccines

Functional, Immunological and Three-Dimensional Analysis of Chemically Synthesised Sporozoite Peptides as Components of a Fully-Effective Antimalarial Vaccine

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