Disruption of endocytosis through chemical inhibition of clathrin heavy chain function

W. Dejonghe, I. Sharma, B. Denoo, S. De Munck, Q. Lu, K. Mishev, H. Bulut, E. Mylle, R. De Rycke, M.K. Vasileva, D.V. Savatin, W. Nerinckx, A. Staes, A. Drozdzecki, D. Audenaert, K. Yperman, A. Madder, J. Friml, D. Van Damme, K. Gevaert, V. Haucke, S.N. Savvides, J. Winne, E. Russinova, Nature Chemical Biology (2019).

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Abstract
Clathrin-mediated endocytosis (CME) is a highly conserved and essential cellular process in eukaryotic cells, but its dynamic and vital nature makes it challenging to study using classical genetics tools. In contrast, although small molecules can acutely and reversibly perturb CME, the few chemical CME inhibitors that have been applied to plants are either ineffective or show undesirable side effects. Here, we identify the previously described endosidin9 (ES9) as an inhibitor of clathrin heavy chain (CHC) function in both Arabidopsis and human cells through affinity-based target isolation, in vitro binding studies and X-ray crystallography. Moreover, we present a chemically improved ES9 analog, ES9-17, which lacks the undesirable side effects of ES9 while retaining the ability to target CHC. ES9 and ES9-17 have expanded the chemical toolbox used to probe CHC function, and present chemical scaffolds for further design of more specific and potent CHC inhibitors across different systems.
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2019-04-22
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Nature Chemical Biology
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Dejonghe W, Sharma I, Denoo B, et al. Disruption of endocytosis through chemical inhibition of clathrin heavy chain function. Nature Chemical Biology. 2019. doi:10.1038/s41589-019-0262-1
Dejonghe, W., Sharma, I., Denoo, B., De Munck, S., Lu, Q., Mishev, K., … Russinova, E. (2019). Disruption of endocytosis through chemical inhibition of clathrin heavy chain function. Nature Chemical Biology. https://doi.org/10.1038/s41589-019-0262-1
Dejonghe, Wim, Isha Sharma, Bram Denoo, Steven De Munck, Qing Lu, Kiril Mishev, Haydar Bulut, et al. “Disruption of Endocytosis through Chemical Inhibition of Clathrin Heavy Chain Function.” Nature Chemical Biology, 2019. https://doi.org/10.1038/s41589-019-0262-1.
W. Dejonghe et al., “Disruption of endocytosis through chemical inhibition of clathrin heavy chain function,” Nature Chemical Biology, 2019.
Dejonghe W, Sharma I, Denoo B, De Munck S, Lu Q, Mishev K, Bulut H, Mylle E, De Rycke R, Vasileva MK, Savatin DV, Nerinckx W, Staes A, Drozdzecki A, Audenaert D, Yperman K, Madder A, Friml J, Van Damme D, Gevaert K, Haucke V, Savvides SN, Winne J, Russinova E. 2019. Disruption of endocytosis through chemical inhibition of clathrin heavy chain function. Nature Chemical Biology.
Dejonghe, Wim, et al. “Disruption of Endocytosis through Chemical Inhibition of Clathrin Heavy Chain Function.” Nature Chemical Biology, Springer Nature, 2019, doi:10.1038/s41589-019-0262-1.

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