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.