title: Synthesis of potent chemical inhibitors of dynamin GTPase.
abstract: Dynamin is a key regulatory protein in clathrin mediated endocytosis. Compared to genetic or immunological tools, small chemical dynamin inhibitors such as dynasore have the potential to study the dynamic nature of endocytic events in cells. Dynasore inhibits dynamin GTPase activity and transferrin uptake at IC(50) approximately 15 microM but use in some biological applications requires more potent inhibitor than dynasore. Here, we chemically modified the side chains of dynasore and found that two derivatives, DD-6 and DD-11 more potently inhibited transferrin uptake (IC(50): 4.00 microM for DD-6, 2.63 microM for DD-11) and dynamin GTPase activity (IC(50): 5.1 microM for DD-6, 3.6 microM for DD-11) than dynasore. The effect was reversible and they were washed more rapidly out than dynasore. TIRF microscopy showed that they stabilize the clathrin coats on the membrane. Our results indicated that new dynasore derivatives are more potent inhibitor of dynamin, displaying promise as leads for the development of more effective analogues for broader biological applications.
authors.affiliation: Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, South Korea.
authors.forename: Suho
authors.initials: S
authors.lastname: Lee
authors.forename: Kwan-Young
authors.initials: KY
authors.lastname: Jung
authors.forename: Joohyun
authors.initials: J
authors.lastname: Park
authors.forename: Joong-Heui
authors.initials: JH
authors.lastname: Cho
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: Sunghoe
authors.initials: S
authors.lastname: Chang
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D002966:Clathrin / Q000378:metabolism; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004705:Endocytosis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism
chemical_list: D002966:Clathrin; C553342:DD-11 compound; C553341:DD-6 compound; D004791:Enzyme Inhibitors; D006835:Hydrazones; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D014168:Transferrin; D034281:Dynamins