High-Throughput Screening Platform To Identify Inhibitors of Protein Synthesis with Potential for the Treatment of Malaria

Fabio Tamaki, Fabio Fisher, Rachel Milne, Fernando Sánchez-Román Terán, Natalie Wiedemar, Karolina Wrobel, Darren Edwards, Hella Baumann, Ian H. Gilbert, Beatriz Baragana, Jake Baum, Susan Wyllie (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
89 Downloads (Pure)

Abstract

Artemisinin-based combination therapies have been crucial in driving down the global burden of malaria, the world’s largest parasitic killer. However, their efficacy is now threatened by the emergence of resistance in Southeast Asia and sub-Saharan Africa. Thus, there is a pressing need to develop new antimalarials with diverse mechanisms of action. One area of Plasmodium metabolism that has recently proven rich in exploitable antimalarial targets is protein synthesis, with a compound targeting elongation factor 2 now in clinical development and inhibitors of several aminoacyl-tRNA synthetases in lead optimization. Given the promise of these components of translation as viable drug targets, we rationalized that an assay containing all functional components of translation would be a valuable tool for antimalarial screening and drug discovery. Here, we report the development and validation of an assay platform that enables specific inhibitors of Plasmodium falciparum translation (PfIVT) to be identified. The primary assay in this platform monitors the translation of a luciferase reporter in a P. falciparum lysate-based expression system. Hits identified in this primary assay are assessed in a counterscreen assay that enables false positives that directly interfere with the luciferase to be triaged. The remaining hit compounds are then assessed in an equivalent human IVT assay. This platform of assays was used to screen MMV’s Pandemic and Pathogen Box libraries, identifying several selective inhibitors of protein synthesis. We believe this new high-throughput screening platform has the potential to greatly expedite the discovery of antimalarials that act via this highly desirable mechanism of action.
Original languageEnglish
Article numbere00237-22
Number of pages13
JournalAntimicrobial Agents and Chemotherapy
Volume66
Issue number6
Early online date1 Jun 2022
DOIs
Publication statusPublished - Jun 2022

Keywords

  • Plasmodium
  • malaria
  • in vitro translation
  • protein synthesis
  • drug discovery
  • antimalarials

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Infectious Diseases
  • Pharmacology

Fingerprint

Dive into the research topics of 'High-Throughput Screening Platform To Identify Inhibitors of Protein Synthesis with Potential for the Treatment of Malaria'. Together they form a unique fingerprint.

Cite this