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Accession Number
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ADA564153
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Title
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Discovery and Testing of Ricin Therapeutics.
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Publication Date
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Jun 2012
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Media Count
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13p
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Personal Author
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D. Tortorella V. Redmann
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Abstract
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Ricin is an extremely potent A-B toxin that is transported from the cell surface to the cytosol where it inactivates ribosomes leading to cell death. Ricin access to the cytosol is dependent on its transport from the cell surface to the ER lumen. We have established a ricin A chain dislocation assay using enzymatic attenuated ricin A chain molecules (RTAE177D and RTAdelta). The ricin A chains undergoes a rapid transport across the ER membrane and is eventually degraded by the proteasome. The instability of ricin A chain was developed into a high-throughput screen to identify chemicals that block ricin transport. A green fluorescent protein (GFP) ricin chimera was created to screen chemical libraries in ricin dislocation inhibitors. Using a high content screen, we have screened a small bioactive FDA -approved chemical library consisting of 2080 compounds and >35,000 compounds from a large chemical library referred to as L1. Presently, we have identified at least eight diverse family of compounds that increased the stability of the ricin-GFP chimera. Secondary assays have confirmed the stability of ricin and other cellular degradation substrates. The data demonstrate that these chemicals could be used to block ricin and may be effective against other pathogens and human diseases.
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Keywords
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Cell death
Cells(Biology)
Chemical inhibitors
Cytosol
Death
Diseases
Dislocation
Enzymes
Er lumen
Fluorescent-based cell assay
High-content screen
Pathogenic microorganisms
Ricin
Ricin toxin
Small weight compounds
Therapy
Toxins and antitoxins
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Source Agency
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Non Paid ADAS
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NTIS Subject Category
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57E - Clinical Medicine
74D - Chemical, Biological, & Radiological Warfare
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Corporate Author
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Mount Sinai School of Medicine, New York.
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Document Type
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Technical report
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Title Note
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Final rept. 17 May 2010-16 May 2012.
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NTIS Issue Number
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1302
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Contract Number
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W81XWH-10-2-0048
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