Quantification of Plasmodium falciparum HRP-2 as an alternative method to [3H]hypoxanthine incorporation to measure the parasite reduction ratio in vitro

de Carvalho, Laís Pessanha; Niepoth, Elena; Mavraj-Husejni, Arbreshe; Kreidenweiss, Andrea; Herrmann, Jennifer; Müller, Rolf; Knaab, Tanja; Burckhardt, Bjoern B.; Kurz, Thomas; Held, Jana

doi:10.1016/j.ijantimicag.2023.106894

International Journal of Antimicrobial Agents

2023

DOI: 10.1016/j.ijantimicag.2023.106894

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Quantification of Plasmodium falciparum HRP-2 as an alternative method to [3H]hypoxanthine incorporation to measure the parasite reduction ratio in vitro

Laís Pessanha de Carvalho,

Elena Niepoth,

Arbreshe Mavraj-Husejni

et al.

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Cited by 3 publications

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“…The PRR, but also other measures of drug activity, including IC 50 assays, are often quantified using incorporation of [ 3 H]-hypoxanthine into DNA of replicating parasites. Due to its robustness and excellent signal-to-noise ratio and despite relying on radioactive material, [ 3 H]-hypoxanthine incorporation remains a gold standard for measuring parasite development and survival. − Alternative quantification methods that perform equally well as the [ 3 H]-hypoxanthine-based assay and do not require the handling of radioactive substances would clearly aid antimalarial drug discovery and development.…”

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confidence: 99%

Next Generation Chemiluminescent Probes for Antimalarial Drug Discovery

Hellingman,

Sifoniou,

Buser

et al. 2024

ACS Infect. Dis.

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Malaria is caused by parasites of the Plasmodium genus and remains one of the most pressing human health problems. The spread of parasites resistant to or partially resistant to single or multiple drugs, including frontline antimalarial artemisinin and its derivatives, poses a serious threat to current and future malaria control efforts. In vitro drug assays are important for identifying new antimalarial compounds and monitoring drug resistance. Due to its robustness and ease of use, the [ 3 H]-hypoxanthine incorporation assay is still considered a gold standard and is widely applied, despite limited sensitivity and the dependence on radioactive material. Here, we present a first-of-its-kind chemiluminescence-based antimalarial drug screening assay. The effect of compounds on P. falciparum is monitored by using a dioxetane-based substrate (AquaSpark β-D-galactoside) that emits highintensity luminescence upon removal of a protective group (β-D-galactoside) by a transgenic β-galactosidase reporter enzyme. This biosensor enables highly sensitive, robust, and cost-effective detection of asexual, intraerythrocytic P. falciparum parasites without the need for parasite enrichment, washing, or purification steps. We are convinced that the ultralow detection limit of less than 100 parasites of the presented biosensor system will become instrumental in malaria research, including but not limited to drug screening.

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confidence: 99%

Next Generation Chemiluminescent Probes for Antimalarial Drug Discovery

Hellingman,

Sifoniou,

Buser

et al. 2024

ACS Infect. Dis.

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The problem of antimalarial resistance and its implications for drug discovery

Schäfer,

Pessanha de Carvalho,

Inoue

et al. 2023

Expert Opinion on Drug Discovery

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An adaptable, fit-for-purpose screening approach with high-throughput capability to determine speed of action and stage specificity of anti-malarial compounds

Duffy,

Sleebs,

Avery

2024

Antimicrob Agents Chemother

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A revamped in vitro compound identification and activity profiling approach is required to meet the large unmet need for new anti-malarial drugs to combat parasite drug resistance. Although compound hit identification utilizing high-throughput screening of large compound libraries is well established, the ability to rapidly prioritize such large numbers for further development is limited. Determining the speed of action of anti-malarial drug candidates is a vital component of malaria drug discovery, which currently occurs predominantly in lead optimization and development. This is due in part to the capacity of current methods which have low throughput due to the complexity and labor intensity of the approaches. Here, we provide an adaptable screening paradigm utilizing automated high content imaging, including the development of an automated schizont maturation assay, which collectively can identify anti-malarial compounds, classify activity into fast and slow acting, and provide an indication of the parasite stage specificity, with high-throughput capability. By frontloading these critical biological parameters much earlier in the drug discovery pipeline, it has the potential to reduce lead compound attrition rates later in the development process. The capability of the approach in its alternative formats is demonstrated using three Medicines for Malaria Venture open access compound “boxes,” namely Pathogen Box (malaria set—125 compounds), Global Health Priority Box [Malaria Box 2 (80 compounds) and zoonotic neglected diseases (80 compounds)], and the Pandemic Response Box (400 compounds). From a total of 685 compounds tested, 79 were identified as having fast ring-stage-specific activity comparable to that of artemisinin and therefore of high priority for further consideration and development.

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Quantification of Plasmodium falciparum HRP-2 as an alternative method to [3H]hypoxanthine incorporation to measure the parasite reduction ratio in vitro

Cited by 3 publications

References 34 publications

Next Generation Chemiluminescent Probes for Antimalarial Drug Discovery

Next Generation Chemiluminescent Probes for Antimalarial Drug Discovery

The problem of antimalarial resistance and its implications for drug discovery

An adaptable, fit-for-purpose screening approach with high-throughput capability to determine speed of action and stage specificity of anti-malarial compounds

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