Journal article

Publication year: 2012

Pages: 738-751

Journal: Journal of Biomolecular Screening

Volume number: 17

Issue number: 6

ISSN: 1087-0571

eISSN: 1552-454X

Open access status: Hybrid

DOI Link: https://doi.org/10.1177/1087057112442382

Publisher: SAGE Publications (UK and US)

Abstract: 
Plasmodium falciparum causes severe malaria infections in millions of people every year. The parasite is developing resistance to the most common antimalarial drugs, which creates an urgent need for new therapeutics. A promising and attractive target for antimalarial drug design is the bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (PfGluPho) of P. falciparum, which catalyzes the key step in the parasites' pentose phosphate pathway. In this study, we describe the development of a high-throughput screening assay to identify small-molecule inhibitors of recombinant PfGluPho. The optimized assay was used to screen three small-molecule compound libraries-namely, LOPAC (Sigma-Aldrich, 1280 compounds), Spectrum (MicroSource Discovery Systems, 1969 compounds), and DIVERSet (ChemBridge, 49 971 compounds). These pilot screens identified 899 compounds that inhibited PfGluPho activity by at least 50%. Selected compounds were further studied to determine IC50 values in an orthogonal assay, the type of inhibition and reversibility, and effects on P. falciparum growth. Screening results and follow-up studies for selected PfGluPho inhibitors are presented. Our high-throughput screening assay may provide the basis to identify novel and urgently needed antimalarial drugs.

Harvard Citation style: Preuss, J., Hedrick, M., Sergienko, E., Pinkerton, A., Mangravita-Novo, A., Smith, L., et al. (2012) High-Throughput Screening for Small-Molecule Inhibitors of Plasmodium falciparum Glucose-6-Phosphate Dehydrogenase 6-Phosphogluconolactonase, Journal of Biomolecular Screening, 17(6), pp. 738-751. https://doi.org/10.1177/1087057112442382

APA Citation style: Preuss, J., Hedrick, M., Sergienko, E., Pinkerton, A., Mangravita-Novo, A., Smith, L., Marx, C., Fischer, E., Jortzik, E., Rahlfs, S., Becker, K., & Bode, L. (2012). High-Throughput Screening for Small-Molecule Inhibitors of Plasmodium falciparum Glucose-6-Phosphate Dehydrogenase 6-Phosphogluconolactonase. Journal of Biomolecular Screening. 17(6), 738-751. https://doi.org/10.1177/1087057112442382