Nonphosphate Inhibitors of IspE Protein, a Kinase in the Non‐Mevalonate Pathway for Isoprenoid Biosynthesis and a Potential Target for Antimalarial Therapy

The discovery of the non-mevalonate pathway for the biosynthesis of the isoprenoid precursors isopentenyl diphosphate (IPP, 1) and dimethylallyl diphosphate (DMAPP, 2) in the 1990s opened the way for new approaches in the fight against infectious diseases. This pathway starts with the condensation of pyruvate 3 and glyceraldehyde 3-phosphate 4 and is used exclusively by pathogenic bacteria such as Mycobacterium tuberculosis, and by the protozoan Plasmodium parasites (Scheme 1). Mammals, on the other hand, use the alternative mevalonate pathway. Hence, the development of small-molecule inhibitors for the enzymes of the nonmevalonate pathway constitutes a novel approach in the treatment of important infectious diseases. Malaria is without a doubt the most important and devastating tropical disease with 300–500 million clinical cases and between one and three million deaths a year. In light of the emergence of drug and insecticide resistance, the need for medicines with a novel mode of action is ever increasing. Inhibition of the enzymes of the non-mevalonate pathway by low-molecular-weight ligands constitutes a true challenge. The active sites for complexation and transformation of their phosphateand diphosphate-based substrates are highly polar and do not offer much concave hydrophobic surface. Correspondingly, most of the few inhibitors known today are phosphates or phosphonates, such as the best-known example, Fosmidomycin, which binds to IspC (1-deoxy-d-xylulose 5phosphate reductoisomerase, EC 1.1.1.267) and is currently in clinical trials. We selected the kinase IspE (4-diphosphocytidyl-2C-methyld-erythritol (CDP-ME) kinase, EC 2.7.1.148) in the center of the non-mevalonate pathway as a target for structure-based inhibitor design. IspE catalyzes the phosphorylation of the 2-OH group of 4-diphosphocytidyl-2C-methyl-d-erythritol (5) forming 4-diphosphocytidyl-2C-methyl-d-erythritol-2-phosphate (6) (Scheme 1). Two X-ray crystal structures have been published; the apoenzyme of Thermus thermophilus (1.7 A resolution, Protein Data Bank (PDB) code: 1UEK) and a ternary complex of

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