Abstract
Throughout the last decade, efforts to identify and develop effective inhibitors of the ricin toxin have focused on targeting its N-glycosidase activity. Alternatively, molecules disrupting intracellular trafficking have been shown to block ricin toxicity. Several research teams have recently developed high-throughput phenotypic screens for small molecules acting on the intracellular targets required for entry of ricin into cells. These screens have identified inhibitory compounds that can protect cells, and sometimes even animals against ricin. We review these newly discovered cellular inhibitors of ricin intoxication, discuss the advantages and drawbacks of chemical-genetics approaches, and address the issues to be resolved so that the therapeutic development of these small-molecule compounds can progress.
Highlights
Throughout the last decade, efforts to identify and develop effective inhibitors of the ricin toxin have focused on targeting its N-glycosidase activity
Ricin has been used for the design of immunotoxins against tumor cells, non-specific toxicity prevented those to reach approval for cancer therapy
To counter the threat displayed by the plant toxin ricin, several therapeutic approaches have been developed
Summary
Characterization of molecules that protect cells against ricin by blocking its intracellular trafficking has revealed compounds that often alter the morphology of the Golgi apparatus. Brefeldin A (BFA, MW: 280.4, Figure 2a) is an isoprenoid fungal metabolite that inhibits ricin toxicity in vitro and protects cells from the cytotoxic effects of ricin and Shiga toxin [26,27,28]. Exo was used as a pharmaceutical tool to study the function of the Golgi apparatus in retrograde toxin trafficking [42,43] These studies showed that Exo. 2 has no effect on trafficking of cholera toxin from the cell surface to the ER [42], but significantly inhibits the delivery of Shiga-toxin to the ER [43]. Molecular-modeling studies suggest that the cyclo-octenyl ring of LG186 compensates for the loss of interaction of the M832L residue of GBF1 with GCA, BFA, and Exo in MDCK cells.
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