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Scientific result | Chemistry | High-throughput screening | CBRN-E threats
The SCBM and SIMoS collaborated to optimize the activity of Retro-1, a benzodiazepine compound, inhibitor of Shiga toxins and ricin, derived from high-throughput biological screening. They succeeded in obtaining an analog 70 times more protective against the cytotoxicity of Shiga toxins, Retro-1.1.
Shiga toxins produced by certain bacteria (Shigella dysenteriae and some strains of Escherichia coli) can lead to foodborne illness, especially in young children, sometimes resulting in bloody diarrhea and, in the most severe cases, hemolytic uremic syndrome (HUS). Following a biological screen (cell activity test) carried out on the SCBM small molecule screening platform, Retro-1, a compound from the benzodiazepine family, showed good efficacy (EC50 = 6 µM) against Shiga toxin. Retro-1 inhibits the toxin by decreasing its intracellular transport by the retrograde route from early endosomes to the Golgi apparatus, preventing access to the latter, a necessary step for the release of its toxic subunit in the cytoplasm of the cells (Stechmann et al. Cell 2010). In this study, researchers undertook an analysis of the structure-activity relationship of Retro-1, in order to increase its toxin-inhibitory effect. As a result, they obtained new, much more active benzodiazepinones, including Retro-1.1, which has an EC50 of 90 nM in cell protection tests, approximately 70 times higher than its parent Retro-1. They have also shown that this compound blocks the retrograde trafficking of Shiga toxin and experiments are underway to decipher its mode of action and identify its cellular target(s).
Knowing that Retro-1 behaves like Retro-2 by blocking intracellular trafficking of the toxin, it would be interesting to test optimized Retro-1 analogues, such as Retro-1.1, against various pathogens, especially viruses such as poxviruses, cytomegalovirus and enterovirus 71, for which Retro-2 derivatives have been shown to be effective. Contact : firstname.lastname@example.org or email@example.com
H. Abdelkafi, A. Michau, V. Pons, F. Ngadjeua, A. Clerget, L. Ait Ouarab, DA. Buisson, D. Montoir, L. Caramelle, D. Gillet, J. Barbier, JC. Cintrat. Structure–Activity Relationship Studies of Retro-1 Analogues against Shiga Toxin. J. Med. Chem. 2020, 63, 15, 8114–8133 http://dx.doi.org/10.1021/acs.jmedchem.0c00298
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.