Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors

Euna Yoo, Barbara H. Stokes, Hanna De Jong, Manu Vanaerschot, T. R.S. Kumar, Nina Lawrence, Mathew Njoroge, Arnold Garcia, Renier Van Der Westhuyzen, Jeremiah D. Momper, Caroline L. Ng, David A. Fidock, Matthew Bogyo

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12 Scopus citations

Abstract

The Plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of the parasite and its contribution to the establishment of resistance to artemisinin (ART)-based therapies. However, because of a similarly essential role for the host proteasome, the key property of any antiproteasome therapeutic is selectivity. Several parasite-specific proteasome inhibitors have recently been reported, however, their selectivity must be improved to enable clinical development. Here we describe screening of diverse libraries of non-natural synthetic fluorogenic substrates to identify determinants at multiple positions on the substrate that produce enhanced selectivity. We find that selection of an optimal electrophilic "warhead" is essential to enable high selectivity that is driven by the peptide binding elements on the inhibitor. We also find that host cell toxicity is dictated by the extent of coinhibition of the human β2 and β5 subunits. Using this information, we identify compounds with over 3 orders of magnitude selectivity for the parasite enzyme. Optimization of the pharmacological properties resulted in molecules that retained high potency and selectivity, were soluble, sufficiently metabolically stable and orally bioavailable. These molecules are highly synergistic with ART and can clear parasites in a mouse model of infection, making them promising leads as antimalarial drugs.

Original languageEnglish (US)
Pages (from-to)11424-11437
Number of pages14
JournalJournal of the American Chemical Society
Volume140
Issue number36
DOIs
StatePublished - Sep 12 2018

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ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Yoo, E., Stokes, B. H., De Jong, H., Vanaerschot, M., Kumar, T. R. S., Lawrence, N., Njoroge, M., Garcia, A., Van Der Westhuyzen, R., Momper, J. D., Ng, C. L., Fidock, D. A., & Bogyo, M. (2018). Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors. Journal of the American Chemical Society, 140(36), 11424-11437. https://doi.org/10.1021/jacs.8b06656