Inhibition of Leishmanial Protein Kinase by Antileishmanial Drugs

Jonathan D. Berman Walter Reed Army Institute of Research, Division of Experimental Therapeutics, Washington, DC 20307-5100

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Protein kinase was isolated from both amastigotes and promastigotes of Leishmania mexicana amazonensis. Unlike the previously described enzyme from L. donovani promastigotes, activity of the L. mexicana kinases was 2–3 times higher at low ionic strength than at high ionic strength, and was 3–10-fold augmented by removal of endogenous low molecular weight inhibitors. The Km of the L. mexicana kinases was 123–223 µM, compared to the value of 70 µM for the beef heart kinase. Purine nucleoside analogs are potent antileishmanial agents that are phosphorylated to their respective triphosphates. The mechanism of the analogs is thought to involve competition of the triphosphates with ATP. Cordycepin triphosphate inhibited the amastigote, promastigote, and beef heart protein kinases approximately equally. However, the Kis of formycin A triphosphate for the leishmanial kinases (Ki 40–120 µM) were far less than that of the beef heart kinase (Ki 1,380 µM). The mechanisms of certain chemotherapeutic purine nucleosides may involve specific inhibition of leishmanial protein kinase by the nucleoside triphosphate.

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