Building a better dynasore: the Dyngo compounds potently inhibit dynamin and endocytosis

McCluskey, Adam, Daniel, James A., Hadzic, Gordana, Chau, Ngoc, Clayton, Emma L., Mariana, Anna, Whiting, Ainslie, Gorgani, Nick N., Lloyd, Jonathan, Quan, Annie, Moshkanbaryans, Lia, Krishnan, Sai, Perera, Swetha, Chircop, Megan, von Kleist, Lisa, McGeachie, Andrew B., Howes, Mark T., Parton, Robert G., Campbell, Michael, Sakoff, Jennette A., Wang, Xuefeng, Sun, Jian-Yuan, Robertson, Mark J., Deane, Fiona M., Nguyen, Tam H., Meunier, Frederic A., Cousin, Michael A. and Robinson, Phillip J. (2013) Building a better dynasore: the Dyngo compounds potently inhibit dynamin and endocytosis. Traffic, 14 12: 1272-1289. doi:10.1111/tra.12119


Author McCluskey, Adam
Daniel, James A.
Hadzic, Gordana
Chau, Ngoc
Clayton, Emma L.
Mariana, Anna
Whiting, Ainslie
Gorgani, Nick N.
Lloyd, Jonathan
Quan, Annie
Moshkanbaryans, Lia
Krishnan, Sai
Perera, Swetha
Chircop, Megan
von Kleist, Lisa
McGeachie, Andrew B.
Howes, Mark T.
Parton, Robert G.
Campbell, Michael
Sakoff, Jennette A.
Wang, Xuefeng
Sun, Jian-Yuan
Robertson, Mark J.
Deane, Fiona M.
Nguyen, Tam H.
Meunier, Frederic A.
Cousin, Michael A.
Robinson, Phillip J.
Title Building a better dynasore: the Dyngo compounds potently inhibit dynamin and endocytosis
Journal name Traffic   Check publisher's open access policy
ISSN 1398-9219
1600-0854
Publication date 2013-12
Year available 2013
Sub-type Article (original research)
DOI 10.1111/tra.12119
Open Access Status
Volume 14
Issue 12
Start page 1272
End page 1289
Total pages 18
Place of publication Malden, MA, United States
Publisher Wiley-Blackwell Publishing
Collection year 2014
Language eng
Formatted abstract
Dynamin GTPase activity increases when it oligomerizes either into helices in the presence of lipid templates or into rings in the presence of SH3 domain proteins. Dynasore is a dynamin inhibitor of moderate potency (IC50 ~ 15 μM in vitro). We show that dynasore binds stoichiometrically to detergents used for in vitro drug screening, drastically reducing its potency (IC50 = 479 μM) and research tool utility. We synthesized a focused set of dihydroxyl and trihydroxyl dynasore analogs called the Dyngo™ compounds, five of which had improved potency, reduced detergent binding and reduced cytotoxicity, conferred by changes in the position and/or number of hydroxyl substituents. The Dyngo compound 4a was the most potent compound, exhibiting a 37-fold improvement in potency over dynasore for liposome-stimulated helical dynamin activity. In contrast, while dynasore about equally inhibited dynamin assembled in its helical or ring states, 4a and 6a exhibited >36-fold reduced activity against rings, suggesting that they can discriminate between helical or ring oligomerization states. 4a and 6a inhibited dynamin-dependent endocytosis of transferrin in multiple cell types (IC50 of 5.7 and 5.8 μM, respectively), at least sixfold more potently than dynasore, but had no effect on dynamin-independent endocytosis of cholera toxin. 4a also reduced synaptic vesicle endocytosis and activity-dependent bulk endocytosis in cultured neurons and synaptosomes. Overall, 4a and 6a are improved and versatile helical dynamin and endocytosis inhibitors in terms of potency, non-specific binding and cytotoxicity. The data further suggest that the ring oligomerization state of dynamin is not required for clathrin-mediated endocytosis.
Keyword Bulk endocytosis
Drug discovery
Dynamin
High-throughput screening
Small-molecule inhibitors
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Fri, 22 Nov 2013, 11:42:52 EST by Susan Allen on behalf of Institute for Molecular Bioscience