Clusters of bioactive compounds target dynamic endomembrane networks in vivo Journal Article


Author(s): Drakakaki, Georgia; Robert, Stéphanie; Szatmári, Anna-Maria; Brown, Michelle Q; Nagawa, Shingo; Van Damme, Daniël; Leonard, Marylin; Yang, Zhenbiao; Girke, Thomas; Schmid, Sandra L; Russinova, Eugenia; Friml, Jiří; Raikhel, Natasha V; Hicks, Glen R
Article Title: Clusters of bioactive compounds target dynamic endomembrane networks in vivo
Affiliation
Abstract: Endomembrane trafficking relies on the coordination of a highly complex, dynamic network of intracellular vesicles. Understanding the network will require a dissection of cargo and vesicle dynamics at the cellular level in vivo. This is also a key to establishing a link between vesicular networks and their functional roles in development. We used a high-content intracellular screen to discover small molecules targeting endomembrane trafficking in vivo in a complex eukaryote, Arabidopsis thaliana. Tens of thousands of molecules were prescreened and a selected subset was interrogated against a panel of plasma membrane (PM) and other endomembrane compartment markers to identify molecules that altered vesicle trafficking. The extensive image dataset was transformed by a flexible algorithm into a marker-by-phenotype-by-treatment time matrix and revealed groups of molecules that induced similar subcellular fingerprints (clusters). This matrix provides a platform for a systems view of trafficking. Molecules from distinct clusters presented avenues and enabled an entry point to dissect recycling at the PM, vacuolar sorting, and cell-plate maturation. Bioactivity in human cells indicated the value of the approach to identifying small molecules that are active in diverse organisms for biology and drug discovery.
Keywords: Chemical genomics; Endosidin; Endosome; High content screen
Journal Title: PNAS
Volume: 108
Issue 43
ISSN: 1091-6490
Publisher: National Academy of Sciences  
Date Published: 2011-10-25
Start Page: 17850
End Page: 17855
DOI: 10.1073/pnas.1108581108
Open access: no