Drug Discovery Opinion

Ricin, one of the world’s deadliest toxins, was infamously used to assassinate the Bulgarian dissident writer Georgi Markov in 1978 near Waterloo Bridge in London. Markov died a few days after a ricin-filled pellet was fired into his leg using a modified umbrella. It has been estimated that as little as 500 micrograms of ricin could be fatal in humans if delivered by injection. Since ricin is easily extracted from the seeds of castor oil plants which are widely grown as an ornamental species and commercial crop, it has obvious potential for bioterrorist attacks. Until now, there has been no antidote to ricin poisoning, but French researchers have now described the first small molecules that are able to protect mice against its lethal effects.

Ricin and bacterial Shiga-like toxins exert their lethal effects by blocking protein synthesis. The proteins comprise two subunits, the A chain and the B-chain, which are linked by a disulphide bond. The B-chain facilitates cell entry and intracellular transport, and is reductively cleaved to free the A-chain which inactivates ribosomes and shuts down protein synthesis. To reach their cytosolic target, ribosomal RNA, the toxins follow the retrograde transport route from the plasma membrane to the endoplasmic reticulum, via endosomes and the Golgi apparatus.

Using a cell-based screen of over 16,000 compounds, the French team found two compounds that were able to block the transport of the toxins within the cell whilst showing very little cytotoxicity. The two compounds, Retro-1 and Retro-2, were shown to selectively block the intracellular transport of the toxins between early endosomes and the Golgi apparatus. Unlike other compounds that are known to block retrograde transport, Retro-1 and Retro-2 do not affect other intracellular trafficking and do not show any toxicity. Retro-2 was found to fully protect mice against a lethal dose of ricin, but only if administered before the ricin. Since the compounds act on host cell pathways rather than on the toxin itself, they should also defend against the Shiga-like toxins produced by pathogens such as E. coli, Shigella and Cholera.

The study is published in the journal Cell.

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