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

研究成果: ジャーナルへの寄稿記事

70 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)2638-2644
ページ数7
ジャーナルAntimicrobial Agents and Chemotherapy
44
発行部数10
DOI
出版物ステータス出版済み - 1 1 2000

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Hemin
Antimalarials
Polymerization
Plasmodium berghei
Scintillation Counting
Pharmaceutical Chemistry
Vacuoles
Libraries
Parasites
Hemoglobins
Pharmacology
Pharmaceutical Preparations
hemozoin

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

これを引用

Kurosawa, Y., Dorn, A., Kitsuji-Shirane, M., Shimada, H., Satoh, T., Matile, H., ... 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

Hematin polymerization assay as a high-throughput screen for identification of new antimalarial pharmacophores. / Kurosawa, Y.; Dorn, A.; Kitsuji-Shirane, M.; Shimada, H.; Satoh, T.; Matile, H.; Hofheinz, W.; Masciadri, R.; Kansy, M.; Ridley, R. G.

:: Antimicrobial Agents and Chemotherapy, 巻 44, 番号 10, 01.01.2000, p. 2638-2644.

研究成果: ジャーナルへの寄稿記事

Kurosawa, Y, Dorn, A, Kitsuji-Shirane, M, Shimada, H, Satoh, T, Matile, H, Hofheinz, W, Masciadri, R, Kansy, M & Ridley, RG 2000, 'Hematin polymerization assay as a high-throughput screen for identification of new antimalarial pharmacophores', Antimicrobial Agents and Chemotherapy, 巻. 44, 番号 10, pp. 2638-2644. https://doi.org/10.1128/AAC.44.10.2638-2644.2000
Kurosawa, Y. ; Dorn, A. ; Kitsuji-Shirane, M. ; Shimada, H. ; Satoh, T. ; Matile, H. ; Hofheinz, W. ; Masciadri, R. ; Kansy, M. ; Ridley, R. G. / Hematin polymerization assay as a high-throughput screen for identification of new antimalarial pharmacophores. :: Antimicrobial Agents and Chemotherapy. 2000 ; 巻 44, 番号 10. pp. 2638-2644.
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