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 activit...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 mT OR 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.展开更多
A series of new aurone derivatives was prepared by means of a practical route and their anti-vascular smooth muscle cells（VSMC） vegetation activities were evaluated by the 3-（4,5-dimethylthlazol-2-yl）-2,5- dipheny...A series of new aurone derivatives was prepared by means of a practical route and their anti-vascular smooth muscle cells（VSMC） vegetation activities were evaluated by the 3-（4,5-dimethylthlazol-2-yl）-2,5- diphenyltetrazolium bromide（MTT） method with tetrandrine as a positive contrast drug. The structures of the com- pounds were confirmed by 1H NMR, 13C NMR and electrospray ionization mass spectrometry（ESI-MS）. Several new compounds exhibited promising activity against VSMC proliferation and the preliminary structure-activity relation- ships（SAR） were discussed in order to investigate the essential structures required for their bioactivities.展开更多
基金supported by Hong Kong Baptist University (FRG2/ 16–17/007, FRG2/17–18/003, China)the Health and Medical Research Fund (HMRF/14150561, China)+9 种基金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 Macao (MYRG2016-00151ICMS-QRCM and MYRG2018-00187-ICMS, China)a Discovery Project Grant (DP160101682, Australia) from the Australian Research Council
文摘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 mT OR 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.
基金Supported by the National Natural Science Foundation of China(No.81172938)the Program for the Top Science and Technology Innovation Teams of Higher Learning Institutions of Shanxi Province,China+1 种基金the Shanxi Foundation for Overseas Returned,China(No.2008-51)the Program for the Top Young and Middle-aged Innovative Talents of Higher Learning Institutions of Shanxi Province,China
文摘A series of new aurone derivatives was prepared by means of a practical route and their anti-vascular smooth muscle cells（VSMC） vegetation activities were evaluated by the 3-（4,5-dimethylthlazol-2-yl）-2,5- diphenyltetrazolium bromide（MTT） method with tetrandrine as a positive contrast drug. The structures of the com- pounds were confirmed by 1H NMR, 13C NMR and electrospray ionization mass spectrometry（ESI-MS）. Several new compounds exhibited promising activity against VSMC proliferation and the preliminary structure-activity relation- ships（SAR） were discussed in order to investigate the essential structures required for their bioactivities.
