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

Research output: Contribution to journalArticle

6 Citations (Scopus)

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

Fingerprint

Proteasome Inhibitors
Plasmodium
Parasites
Antimalarials
Proteasome Endopeptidase Complex
Molecules
Catalyst selectivity
Substrates
Life Cycle Stages
Fluorescent Dyes
Peptides
Toxicity
Life cycle
Screening
Enzymes
Pharmacology
Therapeutics
Infection
artemisinine

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., ... 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

Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors. / Yoo, Euna; Stokes, Barbara H.; De Jong, Hanna; Vanaerschot, Manu; Kumar, T. R.S.; Lawrence, Nina; Njoroge, Mathew; Garcia, Arnold; Van Der Westhuyzen, Renier; Momper, Jeremiah D.; Ng, Caroline L; Fidock, David A.; Bogyo, Matthew.

In: Journal of the American Chemical Society, Vol. 140, No. 36, 12.09.2018, p. 11424-11437.

Research output: Contribution to journalArticle

Yoo, E, Stokes, BH, De Jong, H, Vanaerschot, M, Kumar, TRS, Lawrence, N, Njoroge, M, Garcia, A, Van Der Westhuyzen, R, Momper, JD, Ng, CL, Fidock, DA & Bogyo, M 2018, 'Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors', Journal of the American Chemical Society, vol. 140, no. 36, pp. 11424-11437. https://doi.org/10.1021/jacs.8b06656
Yoo E, Stokes BH, De Jong H, Vanaerschot M, Kumar TRS, Lawrence N et al. Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors. Journal of the American Chemical Society. 2018 Sep 12;140(36):11424-11437. https://doi.org/10.1021/jacs.8b06656
Yoo, Euna ; Stokes, Barbara H. ; De Jong, Hanna ; Vanaerschot, Manu ; Kumar, T. R.S. ; Lawrence, Nina ; Njoroge, Mathew ; Garcia, Arnold ; Van Der Westhuyzen, Renier ; Momper, Jeremiah D. ; Ng, Caroline L ; Fidock, David A. ; Bogyo, Matthew. / Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors. In: Journal of the American Chemical Society. 2018 ; Vol. 140, No. 36. pp. 11424-11437.
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