Aurone derivatives as Vps34 inhibitors that modulate autophagy

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 huma...

Full description

Bibliographic Details
Main Authors:	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
Format:	Article
Language:	English
Published:	Elsevier 2019-05-01
Series:	Acta Pharmaceutica Sinica B
Online Access:	http://www.sciencedirect.com/science/article/pii/S2211383518307275

id	doaj-b2e5add242e5422e8d5c00b462e65837
record_format	Article
spelling	doaj-b2e5add242e5422e8d5c00b462e658372020-11-25T01:49:48ZengElsevierActa Pharmaceutica Sinica B2211-38352019-05-0193537544Aurone derivatives as Vps34 inhibitors that modulate autophagyGuodong Li0Joshua William Boyle1Chung-Nga Ko2Wu Zeng3Vincent Kam Wai Wong4Jian-Bo Wan5Philip Wai Hong Chan6Dik-Lung Ma7Chung-Hang Leung8State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, ChinaSchool of Chemistry, Monash University, Clayton 3800, AustraliaDepartment of Chemistry, Hong Kong Baptist University, Hong Kong 999077, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, ChinaSchool of Chemistry, Monash University, Clayton 3800, Australia; Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK; Corresponding authors.Department of Chemistry, Hong Kong Baptist University, Hong Kong 999077, China; Corresponding authors.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China; Corresponding authors.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 derivativehttp://www.sciencedirect.com/science/article/pii/S2211383518307275
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	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
spellingShingle	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 Acta Pharmaceutica Sinica B
author_facet	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
author_sort	Guodong Li
title	Aurone derivatives as Vps34 inhibitors that modulate autophagy
title_short	Aurone derivatives as Vps34 inhibitors that modulate autophagy
title_full	Aurone derivatives as Vps34 inhibitors that modulate autophagy
title_fullStr	Aurone derivatives as Vps34 inhibitors that modulate autophagy
title_full_unstemmed	Aurone derivatives as Vps34 inhibitors that modulate autophagy
title_sort	aurone derivatives as vps34 inhibitors that modulate autophagy
publisher	Elsevier
series	Acta Pharmaceutica Sinica B
issn	2211-3835
publishDate	2019-05-01
description	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
url	http://www.sciencedirect.com/science/article/pii/S2211383518307275
work_keys_str_mv	AT guodongli auronederivativesasvps34inhibitorsthatmodulateautophagy AT joshuawilliamboyle auronederivativesasvps34inhibitorsthatmodulateautophagy AT chungngako auronederivativesasvps34inhibitorsthatmodulateautophagy AT wuzeng auronederivativesasvps34inhibitorsthatmodulateautophagy AT vincentkamwaiwong auronederivativesasvps34inhibitorsthatmodulateautophagy AT jianbowan auronederivativesasvps34inhibitorsthatmodulateautophagy AT philipwaihongchan auronederivativesasvps34inhibitorsthatmodulateautophagy AT diklungma auronederivativesasvps34inhibitorsthatmodulateautophagy AT chunghangleung auronederivativesasvps34inhibitorsthatmodulateautophagy
_version_	1725004884826128384

Aurone derivatives as Vps34 inhibitors that modulate autophagy

Similar Items