title: ENOblock, a unique small molecule inhibitor of the non-glycolytic functions of enolase, alleviates the symptoms of type 2 diabetes.
abstract: Type 2 diabetes mellitus (T2DM) significantly impacts on human health and patient numbers are predicted to rise. Discovering novel drugs and targets for treating T2DM is a research priority. In this study, we investigated targeting of the glycolysis enzyme, enolase, using the small molecule ENOblock, which binds enolase and modulates its non-glycolytic 'moonlighting' functions. In insulin-responsive cells ENOblock induced enolase nuclear translocation, where this enzyme acts as a transcriptional repressor. In a mammalian model of T2DM, ENOblock treatment reduced hyperglycemia and hyperlipidemia. Liver and kidney tissue of ENOblock-treated mice showed down-regulation of known enolase target genes and reduced enolase enzyme activity. Indicators of secondary diabetic complications, such as tissue apoptosis, inflammatory markers and fibrosis were inhibited by ENOblock treatment. Compared to the well-characterized anti-diabetes drug, rosiglitazone, ENOblock produced greater beneficial effects on lipid homeostasis, fibrosis, inflammatory markers, nephrotoxicity and cardiac hypertrophy. ENOblock treatment was associated with the down-regulation of phosphoenolpyruvate carboxykinase and sterol regulatory element-binding protein-1, which are known to produce anti-diabetic effects. In summary, these findings indicate that ENOblock has potential for therapeutic development to treat T2DM. Previously considered as a 'boring' housekeeping gene, these results also implicate enolase as a novel drug target for T2DM.
authors.affiliation: New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju, 61005, Republic of Korea.
authors.forename: Haaglim
authors.initials: H
authors.lastname: Cho
authors.affiliation: New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju, 61005, Republic of Korea.
authors.forename: JungIn
authors.initials: J
authors.lastname: Um
authors.affiliation: New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju, 61005, Republic of Korea.
authors.forename: Ji-Hyung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju, 61005, Republic of Korea.
authors.forename: Woong-Hee
authors.initials: WH
authors.lastname: Kim
authors.affiliation: Cell Regeneration Research Center, Department of Cardiology, Cardiovascular Center, Chonnam National University Hospital, 671 Jebong-ro, Dong-gu, Gwangju, 501-757, Korea.
authors.forename: Wan Seok
authors.initials: WS
authors.lastname: Kang
authors.affiliation: Division of Endocrinology and Metabolism, Inha University School of Medicine, 400-711, Republic of Korea.
authors.forename: So Hun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, 540950, Republic of Korea.
authors.forename: Hyung-Ho
authors.initials: HH
authors.lastname: Ha
authors.affiliation: Drug Discovery Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju, 61005, Republic of Korea.
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Cell Regeneration Research Center, Department of Cardiology, Cardiovascular Center, Chonnam National University Hospital, 671 Jebong-ro, Dong-gu, Gwangju, 501-757, Korea.
authors.forename: Young-Keun
authors.initials: YK
authors.lastname: Ahn
authors.affiliation: New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju, 61005, Republic of Korea.
authors.forename: Da-Woon
authors.initials: DW
authors.lastname: Jung
authors.affiliation: New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju, 61005, Republic of Korea.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Williams
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002467:Cell Nucleus / Q000201:enzymology* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D010751:Phosphopyruvate Hydratase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology*
chemical_list: D001549:Benzamides; C000621265:ENOblock; D014227:Triazines; D010751:Phosphopyruvate Hydratase