title: Potencies of human immunodeficiency virus protease inhibitors in vitro against Plasmodium falciparum and in vivo against murine malaria.
abstract: 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.
authors.affiliation: Queensland Institute of Medical Research and Australian Centre for International and Tropical Health and Nutrition, 300 Herston Road, Herston, Queensland 4029, Australia. kathyA@qimr.edu.au
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Andrews
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Madala
authors.forename: John
authors.initials: J
authors.lastname: Ray
authors.forename: David M
authors.initials: DM
authors.lastname: Wyatt
authors.forename: Petrina M
authors.initials: PM
authors.lastname: Hilton
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Melville
authors.forename: Lynette
authors.initials: L
authors.lastname: Beattie
authors.forename: Donald L
authors.initials: DL
authors.lastname: Gardiner
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Stoermer
authors.forename: Tina
authors.initials: T
authors.lastname: Skinner-Adams
authors.forename: Colin
authors.initials: C
authors.lastname: Berry
authors.forename: James S
authors.initials: JS
authors.lastname: McCarthy
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry; D001665:Binding Sites; D003460:Crystallization; D005260:Female; D017320:HIV Protease Inhibitors / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D006454:Hemoglobins / Q000378:metabolism; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010963:Plasmodium falciparum / Q000187:drug effects*; D011487:Protein Conformation; D015800:Protozoan Proteins
chemical_list: D017320:HIV Protease Inhibitors; D006454:Hemoglobins; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II