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Antimicrobial Agents and Chemotherapy, October 2000, p. 2638-2644, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Hematin Polymerization Assay as a High-Throughput Screen for Identification of New Antimalarial Pharmacophores

Yae Kurosawa,1,2 Arnulf Dorn,3,* Michiko Kitsuji-Shirane,1,4 Hisao Shimada,1 Tomoko Satoh,1,5 Hugues Matile,3 Werner Hofheinz,3 Raffaello Masciadri,3 Manfred Kansy,3 and Robert G. Ridley3,6

Department of Pharmaceutical Screening, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa Prefecture 247,1 New Ceramics Department, Asahi Optical Co., Ltd., Itabashi-ku, Tokyo 174-8639,2 Medical Institute of Bioregulation, Department of Molecular and Cellular Biology, Kyushu University, 3-1-1 Maidaishi, Higashi-ku Fukuoka, Fukuoka 812-8582,4 and Screening Technology, Bayer Yakuhin Research Center Kyoto, 6-5-1-3 Kunimidai, Soraku-gun, Kyoto,5 Japan, and Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., CH-4070 Basel,3 and Drug Discovery Research, WHO/TDR, World Health Organization, CH-1211 Geneva 27,6 Switzerland

Received 24 January 2000/Returned for modification 13 April 2000/Accepted 28 June 2000

Hematin polymerization is a parasite-specific process that enables the detoxification of heme 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.

* Corresponding author. Mailing address: F. Hoffmann-La Roche Ltd, PRPI-D, Building 70/138, CH-4070 Basel, Switzerland. Phone: (61) 688 84 11. Fax: (61) 688 27 29. E-mail: arnulf.dorn{at}roche.com.

Antimicrobial Agents and Chemotherapy, October 2000, p. 2638-2644, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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