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Issue 10, 2010
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Fine tuning Exo2, a small molecule inhibitor of secretion and retrograde trafficking pathways in mammalian cells

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Abstract

The small molecule 4-hydroxy-3-methoxybenzaldehyde (5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl)hydrazone (Exo2) stimulates morphological changes at the mammalian Golgi and trans-Golgi network that are virtually indistinguishable from those induced by brefeldin A. Both brefeldin A and Exo2 protect cells from intoxication by Shiga(-like) toxins by acting on other targets that operate at the early endosome, but do so at the cost of high toxicity to target cells. The advantage of Exo2 is that it is much more amenable to chemical modification and here we report a range of Exo2 analogues produced by modifying the tetrahydrobenzothienopyrimidine core, the vanillin moiety and the hydrazone bond that links these two. These compounds were examined for the morphological changes they stimulated at the Golgi stack, the trans-Golgi network and the transferrin receptor-positive early endosomes and this activity correlated with their inherent toxicity towards the protein manufacturing ability of the cell and their protective effect against toxin challenge. We have developed derivatives that can separate organelle morphology, target specificity, innate toxicity and toxin protection. Our results provide unique compounds with low toxicity and enhanced specificity to unpick the complexity of membrane trafficking networks.

Graphical abstract: Fine tuning Exo2, a small molecule inhibitor of secretion and retrograde trafficking pathways in mammalian cells

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Publication details

The article was received on 06 Jun 2010, accepted on 01 Jul 2010 and first published on 09 Aug 2010


Article type: Paper
DOI: 10.1039/C0MB00035C
Citation: Mol. BioSyst., 2010,6, 2030-2038
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    Fine tuning Exo2, a small molecule inhibitor of secretion and retrograde trafficking pathways in mammalian cells

    L. J. Guetzoyan, R. A. Spooner, F. Boal, D. J. Stephens, J. M. Lord, L. M. Roberts and G. J. Clarkson, Mol. BioSyst., 2010, 6, 2030
    DOI: 10.1039/C0MB00035C

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