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Antimicrobial Agents and Chemotherapy, November 1998, p. 2973-2977, Vol. 42, No. 11
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Central Role of Hemoglobin Degradation in Mechanisms of Action of 4-Aminoquinolines, Quinoline Methanols, and Phenanthrene Methanols

Mathirut Mungthin,1 Patrick G. Bray,1 Robert G. Ridley,2 and Stephen A. Ward1,*

Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool L69 3BX, United Kingdom,1 and Pharmaceuticals Division, Pharma Research Pre-Clinical, Hoffmann-La Roche, Basel, Switzerland2

Received 17 June 1998/Returned for modification 6 August 1998/Accepted 26 August 1998

We have used a specific inhibitor of the malarial aspartic proteinase plasmepsin I and a nonspecific cysteine proteinase inhibitor to investigate the importance of hemoglobin degradation in the mechanism of action of chloroquine, amodiaquine, quinine, mefloquine (MQ), halofantrine, and primaquine. Both proteinase inhibitors antagonized the antiparasitic activity of all drugs tested with the exception of primaquine. An inhibitor of plasmepsin I, Ro40-4388, reduced the incorporation of radiolabelled chloroquine and quinine into malarial pigment by 95%, while causing a 70% reduction in the incorporation of radiolabelled MQ. Cysteine proteinase inhibitor E64 reduced the incorporation of chloroquine and quinine into malarial pigment by 60 and 40%, respectively. This study provides definitive support for the central role of hemoglobin degradation in the mechanism of action of the 4-aminoquinolines and the quinoline and phenanthrene methanol antimalarials.

* Corresponding author. Mailing address: Department of Pharmacology and Therapeutics, The University of Liverpool, P.O. Box 147, Liverpool L69 3BX, United Kingdom. Phone: 44-0151-794-8218. Fax: 44-0151-794-8217. E-mail: saward{at}liv.ac.uk.

Antimicrobial Agents and Chemotherapy, November 1998, p. 2973-2977, Vol. 42, No. 11
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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