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

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Guetzoyan, Lucie J., Spooner, Robert A. , Boal, Frédéric, Stephens, David J., Lord, Mike (J. Mike), Roberts, Lynne M. and Clarkson, Guy J.. (2010) Fine tuning Exo2, a small molecule inhibitor of secretion and retrograde trafficking pathways in mammalian cells. Molecular BioSystems, Vol.6 (No.10). pp. 2030-2038. ISSN 1742-206X

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Official URL: http://dx.doi.org/10.1039/C0MB00035C

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.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history
Divisions:	Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010) Faculty of Science > Chemistry Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH):	Biological transport, Golgi apparatus, Verocytotoxins
Journal or Publication Title:	Molecular BioSystems
Publisher:	Royal Society of Chemistry
ISSN:	1742-206X
Date:	2010
Volume:	Vol.6
Number:	No.10
Page Range:	pp. 2030-2038
Identification Number:	10.1039/c0mb00035c
Status:	Peer Reviewed
Access rights to Published version:	Restricted or Subscription Access
Funder:	Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Wellcome Trust (London, England)
Grant number:	BB/E012450/1 (BBSRC), 080566Z/06/Z (Wellcome)
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URI:	http://wrap.warwick.ac.uk/id/eprint/4268