Novel Inhibitors of Ornithine Decarboxylase of Leishmania Parasite (LdODC): The Parasite Resists LdODC Inhibition by Overexpression of Spermidine Synthase

摘要

Ornithine decarboxylase (LdODC), a key enzyme in polyamine biosynthesis in Leishmania donovani, catalyzes the conversion of ornithine to putrescine that is finally used for synthesis of spermidine and other polyamines. Inhibition of ornithine decarboxylase is likely to deplete the parasite trypanothione and may result in increased reactive oxygen species (ROS). Sequence as well as structure of LdODC and human ODC shows significant difference; therefore, we have identified novel specific inhibitors of LdODC. These inhibitors are able to inhibit recombinant LdODC and decrease intracellular putrescine concentration showing target specificity. The K-i values of LdODC inhibition do not correlate with IC50 values in Leishmania promastigote possibly due to different stability/pharmacokinetics. These inhibitors, except compound M-5, have only minor effect on Leishmania promastigotes, and IC50 values are several folds higher as compared to K-i values. In case of compound M-5, IC50 value is less than K-i value indicating that the compound may have additional targets. Our studies suggest that the parasite resists these LdODC inhibitors by overexpression of spermidine synthase mRNA.