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2014-12-11 [ PDF ]
A chemical rescue screen identifies a P.falcip. apicoplast inhibitor targeting MEP isoprenoid precursor biosynthesis
Wesley Wu, Zachary Herrera, Danny Ebert, Katie Baska, Seok H. Cho, Joseph L. DeRisi, Ellen Yeh

AAC, 2014

Abstract: The apicoplast is an essential plastid organelle found in Plasmodium spp parasites, which contains several clinically validated anti-malarial drug targets. A chemical rescue screen identified MMV-08138 from the “Malaria Box” library of growth-inhibitory anti-malarial compounds as having specific activity against the apicoplast. MMV-08138 inhibition of blood stage P. falciparum growth is stereospecific and potent, with the most active diastereomer demonstrating an EC50=110 nM. Whole-genome sequencing of 3 drug-resistant parasite populations from two independent selections revealed E688Q and L244I mutations in P. falciparum IspD, an enzyme in the MEP isoprenoid precursor biosynthesis pathway in the apicoplast. The active diastereomer of MMV-08138 directly inhibited PfIspD activity in vitro with an IC50 of 7.0 nM. MMV-08138 is the first PfIspD inhibitor to be identified and, together with heterologously expressed PfIspD, provides the foundation for further development of this promising anti-malarial drug candidate lead. Furthermore, this study validates the use of the apicoplast chemical rescue screen coupled with target elucidation as a discovery tool to identify specific apicoplast-targeting compounds with new mechanisms of action.