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. 2017 Dec 6;3(12):1322–1328. doi: 10.1021/acscentsci.7b00486

Figure 3.

Figure 3

Selenosulfide inhibitors of STEP. (a) Combining the STEP-specific aryl scaffold of previously developed active site directed reversible inhibitors 5 and 6 with the selenosulfide PTP pharmacophore to generate potent STEP selenosulfide inhibitor 7 assayed with or without physiological intracellular concentrations of GSH (1 mM). (b) Irreversible inhibition with 7. STEP (200 nM) and inhibitor 7 (1 μM) (or DMSO control) were incubated for 60 min in the absence of GSH to inhibit enzymatic activity prior to dialysis. The enzymatic activity of STEP was measured using the pNPP assay at 0, 5, and 24 h after dialysis. (c) Reactivation of inhibited STEP by the addition of thiols. STEP (200 nM) and 7 (5 μM) were incubated for 10 min, and following addition of GSH or DTT (1 mM each) or water (no reductant), for another 0, 0.5, 1, and 1.5 h after which enzymatic activity was measured. (d) Structure–activity relationship of STEP selenosulfide inhibitors.