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

Adam McCluskey, James A Daniel, Gordana Hadzic, Ngoc Chau, Emma L Clayton, Anna Mariana, Ainslie Whiting, Nick N Gorgani, Jonathan Lloyd, Annie Quan, Lia Moshkanbaryans, Sai Krishnan, Swetha Perera, Megan Chircop, Lisa von Kleist, Andrew B McGeachie, Mark T Howes, Robert G Parton, Michael Campbell, Jennette A SakoffXuefeng Wang, Jian-Yuan Sun, Mark J Robertson, Fiona M Deane, Tam H Nguyen, Frederic A Meunier, Michael A Cousin, Phillip J Robinson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)1272-89
Number of pages18
Issue number12
Publication statusPublished - Dec 2013


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