Abrin and Immunoneutralization: A Review

Bagaria, Shradha; Karande, Anjali A.

doi:10.1007/978-94-007-6645-7_9-1

Cited by 5 publications

(5 citation statements)

References 49 publications

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“…These processes have been studied for over two decades with a growing number of results that indicate their significance for cell death observed. However, it is still unclear whether the inhibition of protein synthesis is sufficient to induce apoptosis in all cell lines and to what extent other factors are required for the induction of apoptosis [30,205].…”

Section: Cytotoxic Action Of Ricin On Cellsmentioning

confidence: 99%

Intracellular Transport and Cytotoxicity of the Protein Toxin Ricin

Sowa-Rogozińska

Sominka

Nowakowska-Gołacka

et al. 2019

Toxins

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Ricin can be isolated from the seeds of the castor bean plant (Ricinus communis). It belongs to the ribosome-inactivating protein (RIP) family of toxins classified as a bio-threat agent due to its high toxicity, stability and availability. Ricin is a typical A-B toxin consisting of a single enzymatic A subunit (RTA) and a binding B subunit (RTB) joined by a single disulfide bond. RTA possesses an RNA N-glycosidase activity; it cleaves ribosomal RNA leading to the inhibition of protein synthesis. However, the mechanism of ricin-mediated cell death is quite complex, as a growing number of studies demonstrate that the inhibition of protein synthesis is not always correlated with long term ricin toxicity. To exert its cytotoxic effect, ricin A-chain has to be transported to the cytosol of the host cell. This translocation is preceded by endocytic uptake of the toxin and retrograde traffic through the trans-Golgi network (TGN) and the endoplasmic reticulum (ER). In this article, we describe intracellular trafficking of ricin with particular emphasis on host cell factors that facilitate this transport and contribute to ricin cytotoxicity in mammalian and yeast cells. The current understanding of the mechanisms of ricin-mediated cell death is discussed as well. We also comment on recent reports presenting medical applications for ricin and progress associated with the development of vaccines against this toxin.

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Section: Cytotoxic Action Of Ricin On Cellsmentioning

confidence: 99%

Intracellular Transport and Cytotoxicity of the Protein Toxin Ricin

Sowa-Rogozińska

Sominka

Nowakowska-Gołacka

et al. 2019

Toxins

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show abstract

“…Several antibodies against abrin currently exist, including a neutralizing antibody, D6F10, that rescues cells and protects mice from lethal doses of abrin [37,38,39,40], a potential immunotherapeutic antibody A7C4 that prevented toxicity and lethality in mice [41], and human antibodies isolated from phage display libraries [42]; however, peptide capture reagents are more thermally and chemically stable and could therefore be extremely useful for certain applications, such as toxin detection in extreme environments. Other alternatives to standard antibodies do currently exist for abrin or its derivatives.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Roots of Selectivity of Peptide Affinity Reagents for Structurally Similar Ribosomal Inactivating Protein Derivatives

2016

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Peptide capture agents have become increasingly useful tools for a variety of sensing applications due to their ease of discovery, stability, and robustness. Despite the ability to rapidly discover candidates through biopanning bacterial display libraries and easily mature them to Protein Catalyzed Capture (PCC) agents with even higher affinity and selectivity, an ongoing challenge and critical selection criteria is that the peptide candidates and final reagent be selective enough to replace antibodies, the gold-standard across immunoassay platforms. Here, we have discovered peptide affinity reagents against abrax, a derivative of abrin with reduced toxicity. Using on-cell Fluorescence Activated Cell Sorting (FACS) assays, we show that the peptides are highly selective for abrax over RiVax, a similar derivative of ricin originally designed as a vaccine, with significant structural homology to abrax. We rank the newly discovered peptides for strongest affinity and analyze three observed consensus sequences with varying affinity and specificity. The strongest (Tier 1) consensus was FWDTWF, which is highly aromatic and hydrophobic. To better understand the observed selectivity, we use the XPairIt peptide-protein docking protocol to analyze binding location predictions of the individual Tier 1 peptides and consensus on abrax and RiVax. The binding location profiles on the two proteins are quite distinct, which we determine is due to differences in pocket size, pocket environment (including hydrophobicity and electronegativity), and steric hindrance. This study provides a model system to show that peptide capture candidates can be quite selective for a structurally similar protein system, even without further maturation, and offers an in silico method of analysis for understanding binding and down-selecting candidates.

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“…It is thus tempting to assume that the antibody binding to this epitope blocks the active site, thereby directly neutralizing the catalytic activity of abrin. This notion may be supported by the study by Bagaria et al [15] that mapped the epitope of an antiabrin monoclonal neutralizing antibody, D6F10. This antibody binds to Residues T112, G114, and R118 that are located also at the surface of the active site, contrapositioned to Epitope 4.…”

Section: Immunodominant Epitopes Of Abrin Subunit Amentioning

confidence: 82%

“…Here, we found that these residues are members of two of the identified immunodominant epitopes, Epitopes 5 and 6, respectively. Not surprisingly, in the folded form of the toxin, these two epitopes are adjacent to each other ( Figure 2B), and they are positioned distal to the active site; however, to induce cell death, ATA needs to interact with other proteins en route to the cytoplasm (as was shown in detail for ricin subunit A [15]. It is, therefore, possible that binding antibodies to Epitope(s) 5 and/or 6 may interfere with one or more abrin:protein interactions required for ATA cytotoxic performance.…”

Section: Immunodominant Epitopes Of Abrin Subunit Amentioning

confidence: 85%

Mapping Immunodominant Antibody Epitopes of Abrin

et al. 2020

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Abrin, a toxin isolated from the seeds of Abrus precatorius (jequirity pea) is considered a biological threat agent by the Center for Disease Control and Prevention. To date, there is no effective postexposure treatment for abrin poisoning, and efforts are being made to develop an efficient vaccine and measures for postexposure therapy. Epitope mapping is widely applied as an efficient tool for discovering the antigenic moieties of toxins, thus providing invaluable information needed for the development of vaccines and therapies. Aiming to identify the immunodominant epitopes of abrin, several neutralizing antiabrin polyclonal antibodies were screened using a set of 15-mer peptides spanning the amino acid sequence of either the A or B subunits of abrin. Analysis of the antibody-binding pattern revealed 11 linear epitopes for the A subunit and 14 epitopes for the B subunit that are located on the surface of the toxin and thus accessible for antibody interactions. Moreover, the spatial location of several of these epitopes suggests they may block the galactose-binding pockets or the catalytic domain, thus neutralizing the toxin. These findings provide useful information and suggest a possible strategy for the development and design of an improved abrin-based vaccine and therapeutic antibodies.

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Abrin and Immunoneutralization: A Review

Cited by 5 publications

References 49 publications

Intracellular Transport and Cytotoxicity of the Protein Toxin Ricin

Intracellular Transport and Cytotoxicity of the Protein Toxin Ricin

Unraveling the Roots of Selectivity of Peptide Affinity Reagents for Structurally Similar Ribosomal Inactivating Protein Derivatives

Mapping Immunodominant Antibody Epitopes of Abrin

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