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.
Highlights
Target validation has shown that two glycolysis enzymes, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and enolase, possess moonlighting functions that can produce potential anti-diabetic effects[7,8,9]
It was observed that ENOblock treatment reduced enolase activity in the cells (Fig. 1A)
We show for the first time that ENOblock reduces enolase activity and produces numerous beneficial effects in a mammalian model of Type 2 diabetes mellitus (T2DM)
Summary
Target validation has shown that two glycolysis enzymes, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and enolase, possess moonlighting functions that can produce potential anti-diabetic effects[7,8,9]. The novel enolase modulating compound, ENOblock, was shown to induce two potentially anti-diabetic effects: increased glucose uptake and down-regulation of the gluconeogenesis enzyme, phosphoenolpyruvate carboxykinase (Pck-1) in cells and wild-type zebrafish larvae[9,10]. ENOblock treatment produced less adverse side effects in the liver, kidney and heart. These findings implicate enolase as a novel drug target for T2DM and ENOblock as a T2DM drug candidate for clinical development
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