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Antimicrobial Agents and Chemotherapy, February 2006, p. 639-648, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.639-648.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro against Plasmodium falciparum and In Vivo against Murine Malaria

Katherine T. Andrews,1* David P. Fairlie,2 Praveen K. Madala,2 John Ray,3 David M. Wyatt,4 Petrina M. Hilton,1 Lewis A. Melville,1 Lynette Beattie,1 Donald L. Gardiner,1 Robert C. Reid,2 Martin J. Stoermer,2 Tina Skinner-Adams,5 Colin Berry,4 and James S. McCarthy1

Queensland Institute of Medical Research and Australian Centre for International and Tropical Health and Nutrition, 300 Herston Road, Herston, Queensland 4029, Australia,1 Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, Australia,2 Division Clinical Pharmacology and Toxicology, St. Vincents Hospital, Victoria Street, Darlinghurst, New South Wales 2010, Australia,3 Cardiff University, Museum Avenue, Cardiff CF10 3US, Wales, United Kingdom,4 University of Queensland, Department of Medicine, Central Clinical Division, Brisbane 4072, Australia5

Received 3 August 2005/ Returned for modification 27 September 2005/ Accepted 18 October 2005

Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.

* Corresponding author. Mailing address: Queensland Institute of Medical Research and Australian Centre for International and Tropical Health and Nutrition, 300 Herston Road, Herston, Queensland 4029, Australia. Phone: 61-7-3845 3725. Fax: 61-7-3845 3507. E-mail: kathyA{at}qimr.edu.au.

Antimicrobial Agents and Chemotherapy, February 2006, p. 639-648, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.639-648.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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