title: Identification of a novel small molecule targeting UQCRB of mitochondrial complex III and its anti-angiogenic activity.
abstract: Our recent study has shown that ubiquinol-cytochrome c reductase binding protein (UQCRB), the 13.4-kDa subunit of mitochondrial complex III, plays a crucial role in hypoxia-induced angiogenesis via mitochondrial reactive oxygen species (ROS)-mediated signaling. Here we report a new synthetic small molecule targeting the mitochondrial oxygen sensor UQCRB that was identified by pharmacophore-based virtual screening and in vitro and in vivo competition binding analyses. 6-((1-Hydroxynaphthalen-4-ylamino)dioxysulfone)-2H-naphtho[1,8-bc]thiophen-2-one (HDNT) binds to the hydrophobic pocket of UQCRB and potently inhibits in vitro angiogenesis of human umbilical vein endothelial cells without cytotoxicity. Furthermore, the binding of HDNT to UQCRB suppressed mitochondrial ROS-mediated hypoxic signal transduction. These results demonstrated that HDNT is a novel synthetic small molecule targeting UQCRB and exhibits anti-angiogenic activity by modulating the oxygen-sensing function of UQCRB.
authors.affiliation: Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jung
authors.forename: Ki Hyun
authors.initials: KH
authors.lastname: Kim
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003198:Computer Simulation; D014450:Electron Transport Complex III / Q000737:chemistry* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C557886:6-((1-hydroxynaphthalen-4-ylamino)dioxysulfone)-2H-naphtho(1,8-bc)thiophen-2-one; D020533:Angiogenesis Inhibitors; D002352:Carrier Proteins; D006575:Heterocyclic Compounds, 3-Ring; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C027208:ubiquinone-binding proteins; D014450:Electron Transport Complex III