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Volume 16
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10.3390/ph16020163
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Article

The Parasite Reduction Ratio (PRR) Assay Version 2: Standardized Assessment of Plasmodium falciparum Viability after Antimalarial Treatment In Vitro

by
Annabelle Walz
1,2,
Maëlle Duffey
3,
Ghaith Aljayyoussi
3,4,
Sibylle Sax
1,2,
Didier Leroy
3,
Dominique Besson
3,
Jeremy N. Burrows
3,
Mohammed H. Cherkaoui-Rbati
3,
Nathalie Gobeau
3,
Marie-Anne Westwood
5,
Christoph Siethoff
5,
Francisco-Javier Gamo
6,
Pascal Mäser
1,2,† and
Sergio Wittlin
1,2,*,†
1
Swiss Tropical and Public Health Institute, 4123 Allschwil, Switzerland
2
University of Basel, 4001 Basel, Switzerland
3
Medicines for Malaria Venture, 1215 Geneva, Switzerland
4
Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool L3 5QA, UK
5
Swiss BioQuant, 4153 Reinach, Switzerland
6
Global Health Medicines, GlaxoSmithKline I+D, 28760 Madrid, Spain
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this article.
Pharmaceuticals 2023, 16(2), 163; https://doi.org/10.3390/ph16020163
Submission received: 20 December 2022 / Revised: 12 January 2023 / Accepted: 14 January 2023 / Published: 23 January 2023
(This article belongs to the Special Issue Drug Discovery and Evaluation for the Treatment of Parasitic Infections)
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Abstract

With artemisinin-resistant Plasmodium falciparum parasites emerging in Africa, the need for new antimalarial chemotypes is persistently high. The ideal pharmacodynamic parameters of a candidate drug are a rapid onset of action and a fast rate of parasite killing or clearance. To determine these parameters, it is essential to discriminate viable from nonviable parasites, which is complicated by the fact that viable parasites can be metabolically inactive, whilst dying parasites can still be metabolically active and morphologically unaffected. Standard growth inhibition assays, read out via microscopy or [3H] hypoxanthine incorporation, cannot reliably discriminate between viable and nonviable parasites. Conversely, the in vitro parasite reduction ratio (PRR) assay is able to measure viable parasites with high sensitivity. It provides valuable pharmacodynamic parameters, such as PRR, 99.9% parasite clearance time (PCT99.9%) and lag phase. Here we report the development of the PRR assay version 2 (V2), which comes with a shorter assay duration, optimized quality controls and an objective, automated analysis pipeline that systematically estimates PRR, PCT99.9% and lag time and returns meaningful secondary parameters such as the maximal killing rate of a drug (Emax) at the assayed concentration. These parameters can be fed directly into pharmacokinetic/pharmacodynamic models, hence aiding and standardizing lead selection, optimization, and dose prediction.
Keywords: malaria; Plasmodium falciparum; parasite viability; limiting dilution; parasite reduction ratio; PRR; PCT; lag phase; pharmacodynamics; Emax malaria; Plasmodium falciparum; parasite viability; limiting dilution; parasite reduction ratio; PRR; PCT; lag phase; pharmacodynamics; Emax

Share and Cite

MDPI and ACS Style

Walz, A.; Duffey, M.; Aljayyoussi, G.; Sax, S.; Leroy, D.; Besson, D.; Burrows, J.N.; Cherkaoui-Rbati, M.H.; Gobeau, N.; Westwood, M.-A.; et al. The Parasite Reduction Ratio (PRR) Assay Version 2: Standardized Assessment of Plasmodium falciparum Viability after Antimalarial Treatment In Vitro. Pharmaceuticals 2023, 16, 163. https://doi.org/10.3390/ph16020163

AMA Style

Walz A, Duffey M, Aljayyoussi G, Sax S, Leroy D, Besson D, Burrows JN, Cherkaoui-Rbati MH, Gobeau N, Westwood M-A, et al. The Parasite Reduction Ratio (PRR) Assay Version 2: Standardized Assessment of Plasmodium falciparum Viability after Antimalarial Treatment In Vitro. Pharmaceuticals. 2023; 16(2):163. https://doi.org/10.3390/ph16020163

Chicago/Turabian Style

Walz, Annabelle, Maëlle Duffey, Ghaith Aljayyoussi, Sibylle Sax, Didier Leroy, Dominique Besson, Jeremy N. Burrows, Mohammed H. Cherkaoui-Rbati, Nathalie Gobeau, Marie-Anne Westwood, and et al. 2023. "The Parasite Reduction Ratio (PRR) Assay Version 2: Standardized Assessment of Plasmodium falciparum Viability after Antimalarial Treatment In Vitro" Pharmaceuticals 16, no. 2: 163. https://doi.org/10.3390/ph16020163

APA Style

Walz, A., Duffey, M., Aljayyoussi, G., Sax, S., Leroy, D., Besson, D., Burrows, J. N., Cherkaoui-Rbati, M. H., Gobeau, N., Westwood, M.-A., Siethoff, C., Gamo, F.-J., Mäser, P., & Wittlin, S. (2023). The Parasite Reduction Ratio (PRR) Assay Version 2: Standardized Assessment of Plasmodium falciparum Viability after Antimalarial Treatment In Vitro. Pharmaceuticals, 16(2), 163. https://doi.org/10.3390/ph16020163

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