Atomic evidence that modification of H-bonds established with amino acids critical for host-cell binding induces sterile immunity against malaria

Patarroyo, Manuel E.; Cifuentes, Gladys; Piraján, Camilo; Moreno-Vranich, Armando; Vanegas, Magnolia

doi:10.1016/j.bbrc.2010.03.004

Cited by 18 publications

(22 citation statements)

References 30 publications

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“…Native peptide 6746 residue S596 was one of the fundamental binding residues which was modified to produce highly immunogenic and protection-inducing modified HABPs 24216, 23230 and 24214 . This further confirmed our findings that residues establishing H-bonds amongst conserved HABPs in an invasion-relevant molecule are the fundamental residues which must be changed to induce a highly immunogenic and protective immune response against the P. falciparum parasite (Patarroyo et al 2010b).…”

Section: Atomic and Immunological Considerationssupporting

confidence: 87%

“…Studies by Suarez et al (2006) and Patarroyo et al (2010b) have shown that the HLA-DRb1*0403-like allele had higher frequency in the Aotus monkey population being studied, since immunisation and protection studies with these peptides were performed with a sequence from the Aotus HLA-DRb1*0403 chain when using this non-human primate model (Suarez et al 2006;Patarroyo et al 2010a). It was thus decided to carry out molecular modelling analysis, making the corresponding b-chain replacements (residues highlighted in black in the turquoise ribbon shown in Fig.…”

Section: Molecular Modellingmentioning

confidence: 98%

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Protective immunity provided by a new modified SERA protein peptide: its immunogenetic characteristics and correlation with 3D structure

2011

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The serine repeat antigen (SERA) protein is a leading candidate molecule for inclusion as a component in a multi-antigen, multi-stage, minimal subunit-based, chemically synthesised anti-malarial vaccine. Peptides having high red blood cell binding affinity (known as HABPs) have been identified in this protein. The 6733 HABP was located in the C-terminal portion of the 47-kDa fragment while HABP 6754 was located in the C-terminal region of the 56-kDa fragment. These conserved HABPs failed to induce an immune response. Critical red blood cell binding residues and/or their neighbours (assessed by glycine-analogue scanning) were replaced by others having the same mass, volume and surface but different polarity, rendering some of them highly immunogenic when assessed by antibody production against the parasite or its proteins and protection-inducers against experimental challenge with a highly infectious Aotus monkey-adapted Plasmodium falciparum strain. This manuscript presents some modified HABPs as vaccine candidate components for enriching our tailor-made anti-malarial vaccine repertoire, as well as their 3D structure obtained by 1H-NMR displaying a short-structured region, differently from the native ones having random structures.

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Section: Atomic and Immunological Considerationssupporting

confidence: 87%

Section: Molecular Modellingmentioning

confidence: 98%

Protective immunity provided by a new modified SERA protein peptide: its immunogenetic characteristics and correlation with 3D structure

2011

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“…they are not immunogenic nor do they induce protection. (Patarroyo et al, 2010;Patarroyo et al, 2012) The following part of this manuscript only deals with Spz molecules involved in invasion of hepatocytes whose 3D structures have already been determined. The relevant structures include circumsporozoite protein 1 (CSP-1) cHABP 4397 ( 331 IQNSLSTEWSPCSVTCGNGI 350 ) ( Figure 1A, dark yellow) forming a hydrophobic groove or cavity (~600 Å 3 ) where hepatocyte heparan sulphate proteoglycan (HSPG) binds (Doud et al, 2012).…”

Section: Escape Mechanismmentioning

confidence: 99%

Far from the Madding Crowd: the Molecular Basis for Immunological Escape ofPlasmodium falciparum

Patarroyo¹,

Aza-Conde²,

Moreno-Vranich³

et al. 2017

Current Issues in Molecular Biology

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Like Thomas Hardy's famous novel Far from the Madding Crowd, Plasmodium falciparum parasites display their most relevant survival structures (proteins) involved in host cell invasion far away from the immune system's susceptible regions, displaying tremendous genetic variability, to attract the immune response and escape immune pressure. The 3D structure localisation of the conserved amino acid sequences of this deadly parasite's most relevant proteins involved in host cell invasion, as well as the location of the highly polymorphic, h i g h l y i m m u n o g e n i c r e g i o n s , c l e a r l y demonstrates that such structures are far apart, sometimes 90° to 180° opposite, thereby rendering the immune response useless. It is also shown here that these conserved, f u n c t i o n a l l y -r e l e v a n t s t r u c t u r e s a r e immunologically silent, since no immune response has been induced.

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“…cHABPs having amino acid electron-donor atoms like 5501 (MSP-1), 6754 (SERA-5) or 1779 (EBA-175) had random, b-turn or distorted a-helix structures while cHABPs having amino acid electron-acceptor atoms, such as 4325 (AMA-1), 6746 (SERA-5) and 3287 (TRAP), had a regular a-helix structure [91,93]. Interestingly, an association between donor or acceptor HABP and HLADRb* binding capacity was also established; native cHABPs or their modified analogues' amino acid electron-donor atom peptides preferentially bound to HLA-DRb1*0401 and HLADRb1*0701 molecules (DR53 haplotype), while some native cHABPs or their mHABPs containing amino acid electronacceptor atoms bound to HLA-DR52 haplotype molecules, such as DRb1*0301, DRb1*1101 and DRb1*0301 [91,93].…”

Section: Mhabp Structure--function Relationshipmentioning

confidence: 99%

“…It has also been found that critical binding residues for a specific cHABP use H-bonds for interacting with other cHABP residues in the same protein or with host cell membrane receptors; modifying these H-bonds was one of the fundamental clues for inducing an appropriate immune response which could block or destroy parasite function or induce sterile protective immunity against malaria ( Figure 1A) [81,91]. An example of such interaction was observed with thrombospondin-related adhesive protein (TRAP)-derived cHABPs 3287 and 3289 [81], as shown in Figure 1A.…”

Section: Mhabp Structure--function Relationshipmentioning

confidence: 99%

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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Atomic evidence that modification of H-bonds established with amino acids critical for host-cell binding induces sterile immunity against malaria

Cited by 18 publications

References 30 publications

Protective immunity provided by a new modified SERA protein peptide: its immunogenetic characteristics and correlation with 3D structure

Protective immunity provided by a new modified SERA protein peptide: its immunogenetic characteristics and correlation with 3D structure

Far from the Madding Crowd: the Molecular Basis for Immunological Escape ofPlasmodium falciparum

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

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