Potencies of human immunodeficiency virus protease inhibitors in vitro against Plasmodium falciparum and in vivo against murine malaria

被引:123
作者
Andrews, KT
Fairlie, DP
Madala, PK
Ray, J
Wyatt, DM
Hilton, PM
Melville, LA
Beattie, L
Gardiner, DL
Reid, RC
Stoermer, MJ
Skinner-Adams, T
Berry, C
McCarthy, JS
机构
[1] Queensland Inst Med Res, Herston, Qld 4029, Australia
[2] Australian Ctr Int & Trop Hlth & Nutr, Herston, Qld 4029, Australia
[3] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia
[4] St Vincents Hosp, Div Clin Pharmacol & Toxicol, Darlinghurst, NSW 2010, Australia
[5] Univ Cardiff Wales, Cardiff CF10 3US, Wales
[6] Univ Queensland, Dept Med, Cent Clin Div, Brisbane, Qld 4072, Australia
关键词
D O I
10.1128/AAC.50.2.639-648.2006
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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 (31)7). 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 11 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 11 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.
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页码:639 / 648
页数:10
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