Structure and function of the cellular target of the anti-Shiga toxin drug candidate Retro-2.1 – SMERSEC

The new chemical entity Retro-2 has a remarkable capacity to protect cells and mice from Shiga-like toxins, ricin, and a number of viruses, without toxicity. The optimized analogue Retro-2.1 is being developed as a drug candidate to prevent the hemolytic and uremic syndrome, a deadly complication of Shiga toxin-producing Escherichia coli infections, for which there is no treatment. Retro-2 molecules act by blocking the intracellular transport of toxins from early endosomes to the Golgi apparatus. Recently, we identified the target of Retro-2 as Sec16A, a component of the reticulum endoplasmic exit sites. The objectives of this project are to 1) determine the 3D-structure of Sec16A engaged by Retro-2.1 at atomic resolution, 2) understand the resulting mechanism by which this interaction protects cells from intoxication, and 3) evaluate the therapeutic efficacy of formulated Retro-2.1 in mouse models of infections.