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Screening for Inhibitors of Essential Leishmania Glucose Transporters

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Final rept. 1 Jul 2009-30 Jun 2013

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The objective of this project was to identify compounds that selectively inhibit the essential Leishmania glucose transporters and could hence serve as starting points for development of novel anti-leishmanial drugs. A primary high throughput assay and several secondary assays were developed and optimized for this purpose. From the primary assay, 2804 compounds were identified as hits, compounds that strongly inhibited growth of Leishmania mexicana promastigotes insect form parasites grown in culture at 10 M concentration. From the secondary assay that monitored uptake of radiolabeled glucose through the L. mexicana glucose transporter LmxGT2, 162 secondary hits were identified among the 2804 primary hits that strongly inhibited uptake. From a further use of the secondary assay in a dose-response mode, 34 tertiary hits were identified among the 162 secondary hits that inhibited uptake of radiolabeled glucose through LmxGT2 with IC50 values 1 M. These tertiary hits are now being evaluated for those that are selective for LmxGT2 compared to the human glucose transporter GLUT1 and could thus serve as leads from continued drug development. In addition, another secondary assay has been developed that allows screening of the 2804 primary hits for those that potently inhibit growth of intracellular amastigotes by unknown mechanisms of action, the stage of the Leishmania life cycle that invades mammalian macrophages and causes disease. A proof of concept screen of a 69 compound subset of the primary hits revealed 4 compounds 6 that are non-toxic to host macrophages at 1 M but potently inhibit growth of intracellular amastigotes at that concentration. These results suggest that 170 6 of 2804 such amastigote-active compounds may exist among the 2804 primary hits. These results make possible a facile phenotypic screen that can identify multiple compounds with high potency against the disease-causing stage of the Leishmania life cycle, are non-toxic to the

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  • Microbiology
  • Pharmacology

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