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

LJ Guetzoyan, RA Spooner, F Boal, DJ Stephens, JM Lord, LM Roberts, GJ Clarkson

Research output: Contribution to journalArticle (Academic Journal)peer-review

6 Citations (Scopus)

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.
Translated title of the contributionFine tuning Exo2, a small molecule inhibitor of secretion and retrograde trafficking pathways in mammalian cells
Original languageEnglish
Pages (from-to)2030 - 2038
Number of pages9
JournalMolecular bioSystems
Volume6 (10)
DOIs
Publication statusPublished - Oct 2010

Bibliographical note

Publisher: RSC Publishing

Fingerprint Dive into the research topics of 'Fine tuning Exo2, a small molecule inhibitor of secretion and retrograde trafficking pathways in mammalian cells'. Together they form a unique fingerprint.

Cite this