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Screening for Inhibitors of Essential Leishmania Glucose Transporters
Annual rept. 1 Jul 2011-30 Jun 2012
OREGON HEALTH AND SCIENCES UNIV PORTLAND
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The major objective of this project is to identify compounds that function as selective inhibitors of the essential glucose transporters of the parasite Leishmania mexicana. To identify such compounds, a cell growth assay was developed that can be employed in a high-throughput screen HTS for such inhibitors. This assay was employed in a scaling screen of the 2000 compound MicroSource Discovery Spectrum Collection and of the 600,000 compound CBT library at St. Jude Children s Research Hospital with a Z-factor of 0.8. This screen yielded 2800 compounds that qualified as hits in the primary screen of the library, i.e. that inhibited growth of the L. mexicana line expressing the major glucose transporter designated LmxGT2 by 65. These 2800 primary hits were subsequently subjected to a secondary screen in which dose-response curves were performed to asses the ability of each compound to differentially inhibit growth of parasites expressing LmxGT2 versus the human glucose transporter GLUT1. This secondary screen identified 14 compounds that exhibit an IC50 of 1 M and a preferential inhibition of LmxGT2 cells by between 2-13 fold. 4 of these compounds showed significantly more potent inhibition of 3HD-glucose transport by LmxGT2 compared to GLUT1. An alternative and more direct secondary screen is now being developed that measures the ability of each primary hit to inhibit uptake of 3HD-glucose by LmxGT2.
APPROVED FOR PUBLIC RELEASE