Recent work conducted in knockout mouse models or using small molecule modulators of the mitochondrial pyruvate carrier (MPC) have suggested that targeting this protein complex may have efficacy for treating diabetes as insulin sensitizers. To begin to identify other small molecules that interact with the MPC and could potentially be new therapeutic leads, we used a BRET-based MPC reporter assay (reporter sensitive to pyruvate; RESPYR) system that responds to molecules that interact with the pyruvate binding site of the complex. Screening of a 1600 molecule chemical library generated a number of hits for compounds that activated RESPYR activity. Some hits in this unbiased screen confirmed previous reports of MPC interacting drugs, including the insulin-sensitizing thiazolidinediones, pioglitazone and rosiglitazone. Another hit in this screen was Zaprinast, an inhibitor of phosphodiesterase 5 (PDE5). Zaprinast affected RESPYR activity in a dose-dependent manner and at high nM concentrations. Zaprinast also potently inhibited pyruvate-mediated respiration in isolated WT, but not MPC-deficient mitochondria, demonstrating a direct mitochondrial effect and MPC-dependence for this inhibition of pyruvate metabolism. Analyses conducted using other PDE5 inhibitors (Sildenafil, Tadalafil, and Vardenafil) showed no effect on RESPYR activity or mitochondrial respiration. Consistent with the concept that hepatic gluconeogenesis from pyruvate requires mitochondrial pyruvate import, Zaprinast reduced production of glucose from pyruvate in WT, but not MPC-deficient hepatocytes in vitro. Studies are ongoing to determine whether Zaprinast treatment will lower blood glucose in vivo.

In conclusion, these data demonstrate the feasibility of screening for novel MPC interacting compounds to identify novel therapeutics for treating diabetes and other metabolic diseases and also suggests that the orphan drug Zaprinast may be a novel antidiabetic agent.


K.S. McCommis: None. W.T. Hodges: None. Y. Chen: None. K. Chambers: None. B.N. Finck: Board Member; Self; Cirius Therapeutics.

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