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Synthesis of potent chemical inhibitors of dynamin GTPase

Cited 14 time in Web of Science Cited 15 time in Scopus
Authors
Lee, Suho; Jung, Kwan-Young; Park, Joohyun; Chang, Sunghoe; Kim, Yong-Chul; Cho, Joong-Heui
Issue Date
2010-08-15
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Citation
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS; Vol.20 16; 4858-4864
Keywords
DynasoreDynaminGTPaseClathrinEndocytosisTransferrin
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) similar to 15 mu M 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 mu M for DD-6, 2.63 mu M for DD-11) and dynamin GTPase activity (IC(50:) 5.1 mu M for DD-6, 3.6 mu M 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. (c) 2010 Elsevier Ltd. All rights reserved.
ISSN
0960-894X
Language
English
URI
http://hdl.handle.net/10371/76217
DOI
https://doi.org/10.1016/j.bmcl.2010.06.092
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Physiology (생리학교실)Journal Papers (저널논문_생리학교실)
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