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

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Ornithine decarboxylase (LdODC), a key enzyme in polyamine biosynthesis inLeishmania 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 ofLdODC and human ODC shows significant difference; therefore, we have identified novel specific inhibitors ofLdODC. These inhibitors are able to inhibit recombinantLdODC and decrease intracellular putrescine concentration showing target specificity. TheKi values ofLdODC inhibition do not correlate with IC50 values inLeishmaniapromastigote possibly due to different stability/pharmacokinetics. These inhibitors, except compound M-5, have only minor effect onLeishmaniapromastigotes, and IC50 values are several folds higher as compared toKi values. In case of compound M-5, IC50 value is less thanKi value indicating that the compound may have additional targets. Our studies suggest that the parasite resists theseLdODC inhibitors by overexpression of spermidine synthase mRNA.

Novel inhibitors of ornithine decarboxylase of Leishmania donovani are identified. Effect of inhibitors on the parasite survival was studied. Leishmania resists these LdODC inhibitors by over-expression of spermidine synthase.

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