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 5 publications

(1 citation statement)

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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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TKK130 is a 3-Hydroxy-Propanamidine (HPA) with Potent Antimalarial In Vivo Activity and a High Barrier to Resistance

Knaab,

Moritz,

Pessanha de Carvalho

et al. 2024

J. Med. Chem.

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Accelerating Antimalarial Drug Discovery with a New High-Throughput Screen for Fast-Killing Compounds

Sakura,

Ishii,

Yoshida

et al. 2024

ACS Infect. Dis.

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The urgent need for rapidly acting compounds in the development of antimalarial drugs underscores the significance of such compounds in overcoming resistance issues and improving patient adherence to antimalarial treatments. The present study introduces a high-throughput screening (HTS) approach using 1536-well plates, employing Plasmodium falciparum lactate dehydrogenase (PfLDH) combined with nitroreductase (NTR) and fluorescent probes to evaluate inhibition of the growth of the asexual blood stage of malaria parasites. This method was adapted to efficiently assess the speed of action profiling (SAP) in a 384well plate format, streamlining the traditionally time-consuming screening process. By successfully screening numerous compounds, this approach identified fast-killing hits early in the screening process, addressing challenges associated with artemisinin-based combination therapies. The high-throughput SAP method is expected to be of value in continuously monitoring fast-killing properties during structure−activity relationship studies, expediting the identification and development of novel, rapidly acting antimalarial drugs within phenotypic drug discovery campaigns.

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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 5 publications

References 34 publications

Next Generation Chemiluminescent Probes for Antimalarial Drug Discovery

Next Generation Chemiluminescent Probes for Antimalarial Drug Discovery

TKK130 is a 3-Hydroxy-Propanamidine (HPA) with Potent Antimalarial In Vivo Activity and a High Barrier to Resistance

Accelerating Antimalarial Drug Discovery with a New High-Throughput Screen for Fast-Killing Compounds

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