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dc.contributor.authorAndrews, KT
dc.contributor.authorFairlie, DP
dc.contributor.authorMadala, PK
dc.contributor.authorRay, J
dc.contributor.authorWyatt, DM
dc.contributor.authorHilton, PM
dc.contributor.authorMelville, LA
dc.contributor.authorBeattie, L
dc.contributor.authorGardiner, DL
dc.contributor.authorReid, RC
dc.contributor.authorStoermer, MJ
dc.contributor.authorSkinner-Adams, T
dc.contributor.authorBerry, C
dc.contributor.authorMcCarthy, JS
dc.date.accessioned2017-05-03T16:57:41Z
dc.date.available2017-05-03T16:57:41Z
dc.date.issued2006
dc.date.modified2009-12-21T03:16:52Z
dc.identifier.issn0066-4804
dc.identifier.doi10.1128/AAC.50.2.639-648.2006
dc.identifier.urihttp://hdl.handle.net/10072/27836
dc.description.abstractParasite 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.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Society for Microbiology
dc.publisher.placeUnited States
dc.publisher.urihttp://www.asm.org/
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom639
dc.relation.ispartofpageto648
dc.relation.ispartofissue2
dc.relation.ispartofjournalAntimicrobial agents and Chemotherapy
dc.relation.ispartofvolume50
dc.rights.retentionY
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchMedical microbiology
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode3107
dc.subject.fieldofresearchcode3207
dc.subject.fieldofresearchcode3214
dc.titlePotencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro against Plasmodium falciparum and In Vivo against Murine Malaria
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.date.issued2006
gro.hasfulltextNo Full Text
gro.griffith.authorAndrews, Katherine T.
gro.griffith.authorSkinner-Adams, Tina
gro.griffith.authorGardiner, Donald


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