HIV Protease Inhibitors Inhibit the Development of Preerythrocytic-Stage<i>Plasmodium</i>Parasites

Hobbs, Charlotte V.; Voza, Tatiana; Coppi, Alida; Kirmse, Brian; Marsh, Kennan C.; Borkowsky, William; Sinnis, Photini

doi:10.1086/594369

Cited by 58 publications

(65 citation statements)

References 43 publications

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“…Protease inhibitors, such as lopinavir, represent promising therapeutic leads for new antimalarial development. Lopinavir has potent antimalarial activity in vitro and in animal models (4,5), and human studies of lopinavir-treated individuals in areas of endemicity indicate antimalarial potency at clinically relevant doses (2). Importantly, many of the pharmacologic challenges that slow antimalarial development have already been overcome with lopinavir, which is orally bioavailable, available in suspension form (for pediatric use), and suitable for once-daily dosing in combination with ritonavir.…”

Section: Discussionmentioning

confidence: 99%

“…A combination antiviral therapy that includes the HIV protease inhibitor (PI) lopinavir has been found to dramatically decrease malaria incidence in a pediatric clinical population, by 41%, suggesting a direct effect of PIs on parasite replication (2). Indeed, lopinavir has demonstrated in vitro activity (3) against Plasmodium falciparum, the protozoan species responsible for most malaria deaths (1,4). In addition, lopinavir reduces the malaria liver stage burden in infected rhesus monkeys in vivo at clinically relevant concentrations (5).…”

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confidence: 99%

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The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

Kraft

Armstrong

Heitmeier

et al. 2015

Antimicrob Agents Chemother

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Malaria and HIV infection are coendemic in a large portion of the world and remain a major cause of morbidity and mortality. Growing resistance of Plasmodium species to existing therapies has increased the need for new therapeutic approaches. The Plasmodium glucose transporter PfHT is known to be essential for parasite growth and survival. We have previously shown that HIV protease inhibitors (PIs) act as antagonists of mammalian glucose transporters. While the PI lopinavir is known to have antimalarial activity, the mechanism of action is unknown. We report here that lopinavir blocks glucose uptake into isolated malaria parasites at therapeutically relevant drug levels. Malaria parasites depend on a constant supply of glucose as their primary source of energy, and decreasing the available concentration of glucose leads to parasite death. We identified the malarial glucose transporter PfHT as a target for inhibition by lopinavir that leads to parasite death. This discovery provides a mechanistic basis for the antimalarial effect of lopinavir and provides a direct target for novel drug design with utility beyond the HIV-infected population.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

Kraft

Armstrong

Heitmeier

et al. 2015

Antimicrob Agents Chemother

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“…6C). Additionally, PVMresident proteins remain properly localized in cells treated with the known liver stage inhibitors genistein (45), lopinavir (46), and cyclosporin A (47), as well as with the PI3K inhibitor LY294002 and rapamycin (Fig. S4).…”

Section: Eef Elimination and Pvm-resident Protein Mislocalization Arementioning

confidence: 99%

Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins

Hanson

Ressurreição

Buchholz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Residence within a customized vacuole is a highly successful strategy used by diverse intracellular microorganisms. The parasitophorous vacuole membrane (PVM) is the critical interface between Plasmodium parasites and their possibly hostile, yet ultimately sustaining, host cell environment. We show that torins, developed as ATP-competitive mammalian target of rapamycin (mTOR) kinase inhibitors, are fast-acting antiplasmodial compounds that unexpectedly target the parasite directly, blocking the dynamic trafficking of the Plasmodium proteins exported protein 1 (EXP1) and upregulated in sporozoites 4 (UIS4) to the liver stage PVM and leading to efficient parasite elimination by the hepatocyte. Torin2 has single-digit, or lower, nanomolar potency in both liver and blood stages of infection in vitro and is likewise effective against both stages in vivo, with a single oral dose sufficient to clear liver stage infection. Parasite elimination and perturbed trafficking of liver stage PVM-resident proteins are both specific aspects of torin-mediated Plasmodium liver stage inhibition, indicating that torins have a distinct mode of action compared with currently used antimalarials.host-parasite interactions | malaria | protein trafficking | P. falciparum

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“…While the topic is of great significance, the importance of Plasmodium-HIV coinfections will not be discussed here in any further detail. This topic is thoroughly covered in the scientific literature, and there is a wealth of current resources available (46,63,109,276,308,439,557,566,570,591,597). The WHO Regional Office for South-East Asia website (http://www.searo.who.int/index.htm) also covers this topic in great detail.…”

Section: Introductionmentioning

confidence: 99%

Importance of Nonenteric Protozoan Infections in Immunocompromised People

et al. 2010

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SUMMARY There are many neglected nonenteric protozoa able to cause serious morbidity and mortality in humans, particularly in the developing world. Diseases caused by certain protozoa are often more severe in the presence of HIV. While information regarding neglected tropical diseases caused by trypanosomatids and Plasmodium is abundant, these protozoa are often not a first consideration in Western countries where they are not endemic. As such, diagnostics may not be available in these regions. Due to global travel and immigration, this has become an increasing problem. Inversely, in certain parts of the world (particularly sub-Saharan Africa), the HIV problem is so severe that diseases like microsporidiosis and toxoplasmosis are common. In Western countries, due to the availability of highly active antiretroviral therapy (HAART), these diseases are infrequently encountered. While free-living amoebae are rarely encountered in a clinical setting, when infections do occur, they are often fatal. Rapid diagnosis and treatment are essential to the survival of patients infected with these organisms. This paper reviews information on the diagnosis and treatment of nonenteric protozoal diseases in immunocompromised people, with a focus on patients infected with HIV. The nonenteric microsporidia, some trypanosomatids, Toxoplasma spp., Neospora spp., some free-living amoebae, Plasmodium spp., and Babesia spp. are discussed.

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HIV Protease Inhibitors Inhibit the Development of Preerythrocytic-StagePlasmodiumParasites

Cited by 58 publications

References 43 publications

The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins

Importance of Nonenteric Protozoan Infections in Immunocompromised People

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