Select pyrimidinones inhibit the propagation of the malarial parasite,Plasmodium falciparum |
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Authors: | Annette N. Chiang Juan-Carlos Valderramos Raghavan Balachandran Raj J. Chovatiya Brian P. Mead Corinne Schneider Samantha L. Bell Michael G. Klein Donna M. Huryn Xiaojiang S. Chen Billy W. Day David A. Fidock Peter Wipf Jeffrey L. Brodsky |
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Affiliation: | 1. Department of Biological Sciences, University of Pittsburgh, 274 Crawford Hall, Pittsburgh, PA 15260, USA;2. Department of Microbiology, Columbia University, New York, NY 10032, USA;3. Department of Chemistry and Department of Pharmaceutical Sciences, Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA 15260, USA;4. Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA |
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Abstract: | Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC50 values from 30 nM to 1.6 μM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents. |
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