Cancer Institute A national cancer institute
designated cancer center

Matthew Bogyo

Publication Details

  • Validation of the Proteasome as a Therapeutic Target in Plasmodium Using an Epoxyketone Inhibitor with Parasite-Specific Toxicity CHEMISTRY & BIOLOGY Li, H., Ponder, E. L., Verdoes, M., Asbjornsdottir, K. H., Deu, E., Edgington, L. E., Lee, J. T., Kirk, C. J., Demo, S. D., Williamson, K. C., Bogyo, M. 2012; 19 (12): 1535-1545


    The Plasmodium proteasome has been suggested to be a potential antimalarial drug target; however, toxicity of inhibitors has prevented validation of this enzyme in vivo. We report a screen of a library of 670 analogs of the recent US Food and Drug Administration-approved inhibitor, carfilzomib, to identify compounds that selectively kill parasites. We identified one compound, PR3, that has significant parasite killing activity in vitro but dramatically reduced toxicity in host cells. We found that this parasite-specific toxicity is not due to selective targeting of the Plasmodium proteasome over the host proteasome, but instead is due to a lack of activity against one of the human proteasome subunits. Subsequently, we used PR3 to significantly reduce parasite load in Plasmodium berghei infected mice without host toxicity, thus validating the proteasome as a viable antimalarial drug target.

    View details for DOI 10.1016/j.chembiol.2012.09.019

    View details for Web of Science ID 000313087300007

    View details for PubMedID 23142757

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