Hematin polymerization assay as a high-throughput screen for identification of new antimalarial pharmacophores

Y. Kurosawa, A. Dorn, M. Kitsuji-Shirane, H. Shimada, T. Satoh, H. Matile, W. Hofheinz, R. Masciadri, M. Kansy, R. G. Ridley

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Abstract

Hematin polymerization is a parasite-specific process that enables the detoxification of heine following its release in the lysosomal digestive vacuole during hemoglobin degradation, and represents both an essential and a unique pharmacological drug target. We have developed a high-throughput in vitro microassay of hematin polymerization based on the detection of 14C-labeled hematin incorporated into polymeric hemozoin (malaria pigment). The assay uses 96-well filtration microplates and requires 12 h and a Wallac 1450 MicroBeta liquid scintillation counter. The robustness of the assay allowed the rapid screening and evaluation of more than 100,000 compounds. Random screening was complemented by the development of a pharmacophore hypothesis using the 'Catalyst' program and a large amount of data available on the inhibitory activity of a large library of 4-aminoquinolines. Using these methods, we identified 'hit' compounds belonging to several chemical structural classes that had potential antimalarial activity. Follow-up evaluation of the antimalarial activity of these compounds in culture and in the Plasmodium berghei murine model further identified compounds with actual antimalarial activity. Of particular interest was a triarylcarbinol (Ro 06-9075) and a related benzophenone (Ro 22-8014) that showed oral activity in the murine model. These compounds are chemically accessible and could form the basis of a new antimalarial medicinal chemistry program.

Original languageEnglish
Pages (from-to)2638-2644
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume44
Issue number10
DOIs
Publication statusPublished - Jan 1 2000

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Kurosawa, Y., Dorn, A., Kitsuji-Shirane, M., Shimada, H., Satoh, T., Matile, H., Hofheinz, W., Masciadri, R., Kansy, M., & Ridley, R. G. (2000). Hematin polymerization assay as a high-throughput screen for identification of new antimalarial pharmacophores. Antimicrobial Agents and Chemotherapy, 44(10), 2638-2644. https://doi.org/10.1128/AAC.44.10.2638-2644.2000