4.5 Article

High Throughput Screening to Identify Selective and Nonpeptidomimetic Proteasome Inhibitors As Antimalarials

Journal

ACS INFECTIOUS DISEASES
Volume 7, Issue 6, Pages 1818-1832

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.1c00110

Keywords

Plasmodium falciparum; proteasome; nonpeptidomimetic inhibitors; high throughput screening; malaria drug discovery

Funding

  1. Tres Cantos Open Lab Foundation (TCOLF)
  2. GSK
  3. Australian National Health and Medical Research Council

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Through screening compounds, this study identified four chemical families with selectivity for the P. falciparum proteasome, providing a good starting point for the development of new antimalarial drugs.
The Ubiquitin Proteasome System is the main proteolytic pathway in eukaryotic cells, playing a role in key cellular processes. The essentiality of the Plasmodium falciparum proteasome is well validated, underlying its potential as an antimalarial target, but selective compounds are required to avoid cytotoxic effects in humans. Almost 550000 compounds were tested for the inhibition of the chymotrypsin-like activity of the P. falciparum proteasome using a Proteasome-GLO luminescence assay. Hits were confirmed in an orthogonal enzyme assay using Rho110-labeled peptides, and selectivity was assessed against the human proteasome. Four nonpeptidomimetic chemical families with some selectivity for the P. falciparum proteasome were identified and characterized in assays of proteasome trypsin and caspase activities and in parasite growth inhibition assays. Target engagement studies were performed, validating our approach. Hits identified are good starting points for the development of new antimalarial drugs and as tools to better understand proteasome function in P. falciparum.

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