Page 4 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-2]

Target identification of a natural compound that attenuates

atherosclerosis via autophagy-inducing activity

Minjeong Ko¹, Dongjin Lee¹, Ju Yeon Lee², Jin Young Kim², Jong Shin Yoo², Ho Jeong Kwon¹

¹Chemical Genomics Global Research Laboratory, Department of Biotechnology, Yonsei University, Seoul 03722,

Korea, ²Biomedical Omics Group, Korea Basic Science Institute, Cheongwon-Gun, Chungbuk 28119, Korea

Traditional medicinal plants have long been widely used as pharmaceutical agents due to their fascinating biological
activities. Among many medicinal herbs, we recently identified a natural plant D is effective in ameliorating

atherosclerotic plaque formation on ApoE-/- mice. In early stage of atherosclerosis, oxidized low-density

lipoprotein (oxLDL) contributes to the endothelial cell dysfunction as well as macrophage foam cell formation and
previous studies demonstrate that autophagy plays an important role in cardiovascular diseases. Herein, we revealed
that compound YCGX, an active principle of plant D, induces autophagy in time dependent manner via the

suppression of mTOR signaling and increasing TFEB nuclear translocation in HUVECs. Compound YCGX inhibited
ox-LDL-induced foam cell formation in Raw 264.7 macrophage and rescued the autophagy impaired by oxLDL in

HUVECs. To uncover the mode of action of compound YCGX, a combination of DARTS and LC-MS/MS method was
applied to identify the target protein of compound YCGX. Further validation of interaction of compound with target

protein was conducted by DARTS analysis and knockdown study. Collectively, this study provides new insights into
the mechanism of an anti-atherosclerotic natural compound in linking with autophagy.