A Shield Against Ricin

A whole-cell, high-throughput screen of thousands of small molecules has turned up a compound that protects mice from what would normally be a lethal dose of inhaled ricin, according to molecular biologist Daniel Gillet of the Alternative Energies & Atomic Energy Commission, in Gif sur Yvette, France, and cell biologist Ludger Johannes of the Curie Institute, in Paris (Cell 2010, 141, 231).

A large amount of ricin—one of the most toxic chemicals around—is produced as waste during the extraction of oil from castor beans. Already notorious for its use in the assassination of a Bulgarian defector in London during the Cold War, ricin could be dispersed as an aerosol in a bioterrorist attack, notes Vern L. Schramm, a biochemist at Albert Einstein College of Medicine of Yeshiva University, in New York City. Schramm’s own ricin work includes the development of a rapid assay that detects the toxin (Anal. Chem. 2009, 81, 2847).

No proven antidote is available at present. But the compound identified by the French researchers, a tricyclic imine called Retro-2, could be a promising lead for an anti-ricin drug, Schramm says.

Retro-2 works only if injected prior to ricin exposure. Gillet and Johannes are now trying to adapt the compound so it can be administered after exposure to the toxin.

The researchers are also trying to identify Retro-2’s molecular target. They have already determined that the compound blocks transport of ricin within a cell into the cytosol, preventing ricin from disrupting ribosomes that produce proteins needed for the cell to function.

Retro-2 might also offer protection against other toxins that operate via this same route, including Shiga-like toxins produced during infections by enterohemorrhagic Escherichia coli strains, which can cause kidney dysfunction and death. However, testing this hypothesis in mice is proving difficult as a result of regulations on the distribution of toxins. “We have been trying to purchase Shiga toxin 2 to perform our studies for over six months,” Gillet and Johannes note in an e-mail. They hope to obtain the material this year.