Shiga Toxin Therapeutics: Beyond Neutralization
Abstract
:1. Introduction
2. Shiga Toxin Structure and Activity
3. Current State of Shiga Toxin-Targeted Therapeutic Development
4. Beyond Toxin Neutralization
5. The Unfolded Protein Response (UPR)
6. The UPR in Health, Disease, and Shiga Toxicosis
7. Targeting the UPR
8. The Ribotoxic Response
9. Targeting the RSR and Inflammation during Shiga Toxicosis
10. Future Directions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Therapeutic | Drug Class | Target | Mechanism of Action | Animal Models Tested | Clinical Trials Completed | References |
---|---|---|---|---|---|---|
Anti-sera | Polyclonal antibodies | STX, STX2 | Circulating toxin neutralization | Pig, rabbit | None | [49,67] |
Urtoxezumab® | Humanized murine monoclonal antibody | STX2 | Circulating toxin neutralization | Rodent, NHP | Phase II | [50,53] |
cαSTX1 and cαSTX2 | Humanized murine monoclonal antibody | STX1, STX2 | Circulating toxin neutralization | Rodent | Phase I | [54,68] |
Murine anti-STX2 | Murine monoclonal antibody | STX2 | Circulating toxin neutralization | Rodent | None | [52] |
Anti-STX antibodies (various clones) | Human monoclonal antibody | STX1, STX2 | Circulating toxin neutralization | Rodent, pig | None | [51,69,70] |
Camelid anti-STX oligomers | VHH-based neutralizing agent | STX1, STX2 | Circulating toxin neutralization | Rodent | None | [55,71] |
Adenoviral anti-STX2 construct | VHH-based neutralizing agent | STX2 | Circulating toxin neutralization | Rodent, pig | None | [56] |
Tetravalent peptides | Gb3 analogs | STX1, STX2 | Circulating toxin neutralization | Rodent, non-human primate | None | [59,60,61,62] |
Synsorb-Pk® | Silicon dioxide-Gb3 construct | STX1, STX2 | Gastrointestinal toxin neutralization | None | Phase II (failed) | [57,58] |
Retro 1 and Retro 2 | Small molecule inhibitors | STX1, STX2 | Retrograde trafficking inhibitor | Rodent | None | [63,64] |
Manganese | Enzyme cofactor | STX1 | Retrograde trafficking inhibitor | Rodent | None | [65] |
Disease | Cells Type Affected | Outcome | Model System(s) | Reference |
---|---|---|---|---|
Shiga toxicosis following STEC infection | Leukocytes, endothelial cells, renal epithelium, gastrointestinal epithelium | Hemolytic uremic syndrome? Inflammatory cytokine secretion? | Rodent, human monocyte, renal epithelial, and endothelial cells in vitro | [34,44,46,89,90] |
Diabetes mellitus | Pancreatic beta cells | Loss of insulin production | Rodent | [91,92] |
Obesity | Hepatocytes | Hepatic lipidosis, insulin resistance | Rodent, various hepatocyte cell lines in vitro | [91,92] |
Inflammatory Bowel Disease | Intestinal Paneth and goblet cells | Loss of Paneth cells, gastrointestinal inflammation | Rodent | [94,95] |
Neurodegenerative Diseases | Neurons | Neuron dysfunction and degeneration | Rodent | [93] |
Vascular retinopathies | Retinal endothelial and pigmented epithelial cells | Aberrant angiogenesis | Rodent, human retinal endothelial cells and pigmented retinal epithelial cells in vitro | [96] |
Cardiac disease | Cardiomyocytes | Cardiac hypertrophy, arrhythmias, cardiac fibrosis | Rodent, rabbit, human cardiomyocytes in vitro | [97] |
Neoplasia | Malignant cells | Inflammatory cytokine secretion, angiogenesis, tumor survival | Human-mouse xenografts, neoplastic cells in vitro | [98,99,100] |
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Hall, G.; Kurosawa, S.; Stearns-Kurosawa, D.J. Shiga Toxin Therapeutics: Beyond Neutralization. Toxins 2017, 9, 291. https://doi.org/10.3390/toxins9090291
Hall G, Kurosawa S, Stearns-Kurosawa DJ. Shiga Toxin Therapeutics: Beyond Neutralization. Toxins. 2017; 9(9):291. https://doi.org/10.3390/toxins9090291
Chicago/Turabian StyleHall, Gregory, Shinichiro Kurosawa, and Deborah J. Stearns-Kurosawa. 2017. "Shiga Toxin Therapeutics: Beyond Neutralization" Toxins 9, no. 9: 291. https://doi.org/10.3390/toxins9090291