Covalent Inactivation of Isocitrate Lyase by -2,3-Epoxy-Succinic Acid.

The isocitrate lyases (ICL1/2) are essential enzymes of (), the causative agent of tuberculosis. At present, no ICL1/2 inhibitors have progressed to clinical evaluation, despite extensive drug discovery efforts. Herein, we surveyed succinate analogs against ICL1 and found that dicarboxylic acids constrained in their conformations, such as maleic acid, comprise uncompetitive inhibitors of ICL1 and inhibit more potently than their -isomers.