Aurone derivatives as Vps34 inhibitors that modulate autophagy

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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)537–544
Number of pages8
JournalActa Pharmaceutica Sinica B
Volume9
Issue number3
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • Aurone derivative
  • Autophagy
  • Heart or liver damage
  • Inhibitor
  • Natural products
  • Structure-based virtual screening
  • Vesicle trafficking
  • Vps34

Cite this

Li, G., Boyle, J. W., Ko, C. N., Zeng, W., Wong, V. K. W., Wan, J. B., ... Leung, C. H. (2019). Aurone derivatives as Vps34 inhibitors that modulate autophagy. Acta Pharmaceutica Sinica B, 9(3), 537–544. https://doi.org/10.1016/j.apsb.2019.01.016
Li, Guodong ; Boyle, Joshua William ; Ko, Chung Nga ; Zeng, Wu ; Wong, Vincent Kam Wai ; Wan, Jian Bo ; Chan, Philip Wai Hong ; Ma, Dik Lung ; Leung, Chung Hang. / Aurone derivatives as Vps34 inhibitors that modulate autophagy. In: Acta Pharmaceutica Sinica B. 2019 ; Vol. 9, No. 3. pp. 537–544.
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Li, G, Boyle, JW, Ko, CN, Zeng, W, Wong, VKW, Wan, JB, Chan, PWH, Ma, DL & Leung, CH 2019, 'Aurone derivatives as Vps34 inhibitors that modulate autophagy', Acta Pharmaceutica Sinica B, vol. 9, no. 3, pp. 537–544. https://doi.org/10.1016/j.apsb.2019.01.016

Aurone derivatives as Vps34 inhibitors that modulate autophagy. / Li, Guodong; Boyle, Joshua William; Ko, Chung Nga; Zeng, Wu; Wong, Vincent Kam Wai; Wan, Jian Bo; Chan, Philip Wai Hong; Ma, Dik Lung; Leung, Chung Hang.

In: Acta Pharmaceutica Sinica B, Vol. 9, No. 3, 01.01.2019, p. 537–544.

Research output: Contribution to journalArticleResearchpeer-review

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