Synergistic Interactions of the Antiretroviral Protease Inhibitors Saquinavir and Ritonavir with Chloroquine and Mefloquine against
            <i>Plasmodium falciparum</i>
            In Vitro

Skinner‐Adams, Tina S.; Andrews, Katherine Thea; Melville, Lewis; McCarthy, James S.; Gardiner, Donald L.

doi:10.1128/aac.00840-06

Cited by 54 publications

(59 citation statements)

References 22 publications

(20 reference statements)

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“…Antimalarial drug combinations were assessed by isobologram analysis as previously described (58). All assays were performed in 96-well microtiter plates.…”

Section: Methodsmentioning

confidence: 99%

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

Sumanadasa

Goodman

Lucke

et al. 2012

Antimicrob Agents Chemother

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“…Antimalarial drug combinations were assessed by isobologram analysis as previously described (58). All assays were performed in 96-well microtiter plates.…”

Section: Methodsmentioning

confidence: 99%

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

Sumanadasa

Goodman

Lucke

et al. 2012

Antimicrob Agents Chemother

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“…Furthermore, coinfection often leads to severe disease (4,12,19,20). While the effects of antiretroviral therapy on the outcome of malaria infection are not understood, defining these interactions is important (11,13,16,18). Understanding the antimalarial activities of the antiretroviral protease inhibitors (PIs) (reviewed in reference 17), for example, may lead to treatment recommendations that improve clinical outcomes and may also result in the identification of a new antimalarial drug target.…”

mentioning

confidence: 99%

Antimalarial Asexual Stage-Specific and Gametocytocidal Activities of HIV Protease Inhibitors

Peatey

Andrews

Eickel

et al. 2010

Antimicrob Agents Chemother

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The stage-specific antimalarial activities of a panel of antiretroviral protease inhibitors (PIs), including two nonpeptidic PIs (tipranavir and darunavir), were tested in vitro against Plasmodium falciparum. While darunavir demonstrated limited antimalarial activity (effective concentration [EC 50 ], >50 M), tipranavir was active at clinically relevant concentrations (EC 50 , 12 to 21 M). Saquinavir, lopinavir, and tipranavir preferentially inhibited the growth of mature asexual-stage parasites (24 h postinvasion). While all of the PIs tested inhibited gametocytogenesis, tipranavir was the only one to exhibit gametocytocidal activity.The global distributions of HIV and malaria overlap in many regions of the world (reviewed in reference 17). Although data on the number of individuals with both diseases are unavailable, rates of coinfection are likely to be high (7). Furthermore, coinfection often leads to severe disease (4,12,19,20). While the effects of antiretroviral therapy on the outcome of malaria infection are not understood, defining these interactions is important (11,13,16,18). Understanding the antimalarial activities of the antiretroviral protease inhibitors (PIs) (reviewed in reference 17), for example, may lead to treatment recommendations that improve clinical outcomes and may also result in the identification of a new antimalarial drug target.Current data suggest that PIs kill malaria parasites by inhibiting one or more of the six nondigestive vacuole plasmepsins (reviewed in reference 17). In the present study we investigated the stage-specific effects of the PIs on asexual-and sexual-stage Plasmodium falciparum parasites in order to help define the antimalarial target(s) of these drugs and to help guide partner drug choices in the field. To gain additional structure-activity data and information that may be relevant for coinfected individuals we also examined the activities of the nonpeptidic PIs tipranavir (Aptivus) and darunavir (Prezista), new-generation PIs that are active against HIV-1 strains resistant to first generation PIs (9).The antimalarial activities of saquinavir, lopinavir, ritonavir, tipranavir, darunavir, and chloroquine (diphosphate salt; Sigma) were determined as described previously (18). Concentrations required to achieve 10, 50, and 90% growth inhibition (Ϯ the standard error [SE]) were determined by nonlinear regression curve fitting. Each assay was performed in triplicate on at least two separate occasions. Stage-specific growth inhibition assays were performed on synchronized parasite cultures (8) at 0 (ring), 24 (trophozoite), and 36 h (schizont) postsynchronization. Cultures were washed post-drug exposure, resuspended in drug-free medium, and seeded into tissue culture plates containing 0.5 Ci/well [ 3 H]hypoxanthine for 40 h. Incorporation of [ 3 H]hypoxanthine was compared to that in vehicle controls.Drug-induced effects on gametocytogenesis were examined using Pfs16-GFP parasites (3) as previously described (14). Assays were performed in triplicate on three separat...

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“…The P. falciparum genome sequence has revealed the existence of 10 aspartic proteases (plasmepsins), some of which are involved in hemoglobin digestion. 5,13 Plasmepsins inhibition by HIV protease inhibitors has already been suggested. 13 However, which specific enzymes are inhibited remains to be determined.…”

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confidence: 99%

“…2,3 Most of the malaria-endemic countries are also burdened and co-infested by pandemic human immunodeficiency virus. 4,5 An estimated 40 million HIV-infected cases exist in Africa alone with an annual mortality of over 3 million people. 6 Malaria is more prevalent, severe, and recurrent in HIV infected people than those without the virus.…”

mentioning

confidence: 99%

“…Synergistic interactions of other HIV protease inhibitors in combination with chloroquine or mefloquine have been reported. 5 Intraerythrocytic parasite digests hemoglobin and converts the toxic heme generated into non-toxic crystalline hemozoin. The P. falciparum genome sequence has revealed the existence of 10 aspartic proteases (plasmepsins), some of which are involved in hemoglobin digestion.…”

mentioning

confidence: 99%

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HIV Protease Inhibitors, Indinavir or Nelfinavir, Augment Antimalarial Action of Artemisinin in vitro

Mishra¹,

Bhattacharya²,

Sharma³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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Abstract. Most malaria endemic regions are co-infested with HIV infection. Treatment of one may affect outcome of the other in co-infected individuals. HIV protease inhibitors, indinavir or nelfinavir, are important antiretroviral drugs and artemisinin is central to malaria treatment. We show these protease inhibitors augment the antimalarial activity of artemisinin against P. falciparum in vitro .

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Synergistic Interactions of the Antiretroviral Protease Inhibitors Saquinavir and Ritonavir with Chloroquine and Mefloquine against Plasmodium falciparum In Vitro

Cited by 54 publications

References 22 publications

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

Antimalarial Asexual Stage-Specific and Gametocytocidal Activities of HIV Protease Inhibitors

HIV Protease Inhibitors, Indinavir or Nelfinavir, Augment Antimalarial Action of Artemisinin in vitro

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