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

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 deve...

Full description

Bibliographic Details
Main Authors: Baragana, B. (Author), Baum, J. (Author), Baumann, H. (Author), Edwards, D. (Author), Fisher, F. (Author), Gilbert, I.H (Author), Milne, R. (Author), Tamaki, F. (Author), Terán, F.S.-R (Author), Wiedemar, N. (Author), Wrobel, K. (Author), Wyllie, S. (Author)
Format: Article
Language:English
Published: NLM (Medline) 2022
Subjects:
Online Access:View Fulltext in Publisher
LEADER 02812nam a2200337Ia 4500
001 10.1128-aac.00237-22
008 220630s2022 CNT 000 0 und d
020 |a 10986596 (ISSN) 
245 1 0 |a High-Throughput Screening Platform To Identify Inhibitors of Protein Synthesis with Potential for the Treatment of Malaria 
260 0 |b NLM (Medline)  |c 2022 
520 3 |a 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. 
650 0 4 |a antimalarials 
650 0 4 |a drug discovery 
650 0 4 |a in vitro translation 
650 0 4 |a malaria 
650 0 4 |a Plasmodium 
650 0 4 |a protein synthesis 
700 1 0 |a Baragana, B.  |e author 
700 1 0 |a Baum, J.  |e author 
700 1 0 |a Baumann, H.  |e author 
700 1 0 |a Edwards, D.  |e author 
700 1 0 |a Fisher, F.  |e author 
700 1 0 |a Gilbert, I.H.  |e author 
700 1 0 |a Milne, R.  |e author 
700 1 0 |a Tamaki, F.  |e author 
700 1 0 |a Terán, F.S.-R.  |e author 
700 1 0 |a Wiedemar, N.  |e author 
700 1 0 |a Wrobel, K.  |e author 
700 1 0 |a Wyllie, S.  |e author 
773 |t Antimicrobial agents and chemotherapy 
856 |z View Fulltext in Publisher  |u https://doi.org/10.1128/aac.00237-22