Original articles
Guodong Li, Joshua William Boyle, Chung-Nga Ko, Wu Zeng, Vincent Kam Wai Wong, Jian-Bo Wan, Philip Wai Hong Chan, Dik-Lung Ma, Chung-Hang Leung. Aurone derivatives as Vps34 inhibitors that modulate autophagy[J]. Acta Pharmaceutica Sinica B, 2019, 9(3): 537-544

Aurone derivatives as Vps34 inhibitors that modulate autophagy
Guodong Lia, Joshua William Boyleb, Chung-Nga Koc, Wu Zengd, Vincent Kam Wai Wongd, Jian-Bo Wana, Philip Wai Hong Chanb,e, Dik-Lung Mac, Chung-Hang Leunga
a State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China;
b School of Chemistry, Monash University, Clayton 3800, Australia;
c Department of Chemistry, Hong Kong Baptist University, Hong Kong 999077, China;
d State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China;
e Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK
We report in this study the identification of a natural product-like antagonist (1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mTOR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases.
Key words:    Autophagy    Natural products    Vps34    Inhibitor    Structure-based virtual screening    Vesicle trafficking    Heart or liver damage    Aurone derivative   
Received: 2018-12-26     Revised:
DOI: 10.1016/j.apsb.2019.01.016
Funds: This work is supported by Hong Kong Baptist University (FRG2/16-17/007, FRG2/17-18/003, China), the Health and Medical Research Fund (HMRF/14150561, China), the Research Grants Council (HKBU/12301115, China), the National Natural Science Foundation of China (21575121 and 21775131, China), the Hong Kong Baptist University Century Club Sponsorship Scheme 2018 (China), the Interdisciplinary Research Matching Scheme (RC-IRMS/16-17/03, China), Interdisciplinary Research Clusters Matching Scheme (RC-IRCs/17-18/03, China), Innovation and Technology Fund (ITS/260/16FX, China), Matching Proof of Concept Fund (MPCF-001-2017/18, China), Collaborative Research Fund (C5026-16G, China), SKLEBA and HKBU Strategic Development Fund (SKLP_1718_P04, China), the Science and Technology Development Fund, Macao SAR (0072/2018/A2, China), the University of Macau (MYRG2016-00151-ICMS-QRCM and MYRG2018-00187-ICMS, China), and a Discovery Project Grant (DP160101682, Australia) from the Australian Research Council.
Corresponding author: Philip Wai Hong Chan, Dik-Lung Ma, Chung-Hang Leung     Email:phil.chan@monash.edu;edmondma@hkbu.edu.hk;duncanleung@um.edu.mo
Author description:
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Guodong Li
Joshua William Boyle
Chung-Nga Ko
Wu Zeng
Vincent Kam Wai Wong
Jian-Bo Wan
Philip Wai Hong Chan
Dik-Lung Ma
Chung-Hang Leung

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