New Insight into the Mechanism of Accumulation and Intraerythrocytic Compartmentation of Albitiazolium, a New Type of Antimalarial

Wein, Sharon; Ba, Christophe Tran Van; Maynadier, Marjorie; Bordat, Yann; Perez, Julie; Peyrottes, Suzanne; Fraisse, Laurent; Vial, Henri

doi:10.1128/aac.00040-14

Cited by 10 publications

(11 citation statements)

References 43 publications

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“…They are able to cure malaria infections in vivo in mice, primates, and humans, but their clinical development was discontinued because of rapid drug clearance in children (49). T3 concentrates massively in infected erythrocytes in an energy-dependent and saturable process, which underlies its antiplasmodial activity at low nanomolar concentrations (50). We observed a clear increase in the IC 50 values for T3 and T16 in 10G-0.6-2 compared to 10G, which together with silencing of both clag3 genes after only 2 weeks of selection with these drugs demonstrates that P. falciparum can develop resistance to them by changes in the expression of clag3 genes (30,32).…”

Section: Discussionmentioning

confidence: 99%

Identification of Antimalarial Compounds That Require CLAG3 for Their Uptake by Plasmodium falciparum -Infected Erythrocytes

Mira-Martínez

Pickford

Rovira-Graells

et al. 2019

Antimicrob Agents Chemother

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During the intraerythrocytic asexual cycle malaria parasites acquire nutrients and other solutes through a broad selectivity channel localized at the membrane of the infected erythrocyte termed the plasmodial surface anion channel (PSAC). The protein product of the Plasmodium falciparum clonally variant clag3.1 and clag3.2 genes determines PSAC activity. Switches in the expression of clag3 genes, which are regulated by epigenetic mechanisms, are associated with changes in PSAC-dependent permeability that can result in resistance to compounds toxic for the parasite, such as blasticidin S. Here, we investigated whether other antimalarial drugs require CLAG3 to reach their intracellular target and consequently are prone to parasite resistance by epigenetic mechanisms. We found that the bis-thiazolium salts T3 (also known as albitiazolium) and T16 require the product of clag3 genes to enter infected erythrocytes. P. falciparum populations can develop resistance to these compounds via the selection of parasites with dramatically reduced expression of both genes. However, other compounds previously demonstrated or predicted to enter infected erythrocytes through transport pathways absent from noninfected erythrocytes, such as fosmidomycin, doxycycline, azithromycin, lumefantrine, or pentamidine, do not require expression of clag3 genes for their antimalarial activity. This suggests that they use alternative CLAG3-independent routes to access parasites. Our results demonstrate that P. falciparum can develop resistance to diverse antimalarial compounds by epigenetic changes in the expression of clag3 genes. This is of concern for drug development efforts because drug resistance by epigenetic mechanisms can arise quickly, even during the course of a single infection.

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Section: Discussionmentioning

confidence: 99%

Identification of Antimalarial Compounds That Require CLAG3 for Their Uptake by Plasmodium falciparum -Infected Erythrocytes

Mira-Martínez

Pickford

Rovira-Graells

et al. 2019

Antimicrob Agents Chemother

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“…In P. falciparum in vitro cultures, the accumulation of albitiazolium in the intraerythrocytic parasite has been shown to be a rapid process that requires less than 2 h to reach steady state (14) and that is associated with a rapid irreversible toxic effect. However, morphological alterations and the destruction of the parasite were observed only much later (15).…”

Section: Resultsmentioning

confidence: 99%

“…Treatment of Plasmodium with bisthiazolium salts results in delayed morphological alterations and in the destruction of the parasites in vitro (14) and in vivo (Fig. 2F).…”

Section: Discussionmentioning

confidence: 99%

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High Accumulation and In Vivo Recycling of the New Antimalarial Albitiazolium Lead to Rapid Parasite Death

Wein

Taudon

Maynadier

et al. 2017

Antimicrob Agents Chemother

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Albitiazolium is the lead compound of bisthiazolium choline analogues and exerts powerful in vitro and in vivo antimalarial activities. Here we provide new insight into the fate of albitiazolium in vivo in mice and how it exerts its pharmacological activity. We show that the drug exhibits rapid and potent activity and has very favorable pharmacokinetic and pharmacodynamic properties. Pharmacokinetic studies in Plasmodium vinckei-infected mice indicated that albitiazolium rapidly and specifically accumulates to a great extent (cellular accumulation ratio, Ͼ150) in infected erythrocytes. Unexpectedly, plasma concentrations and the area under concentration-time curves increased by 15% and 69% when mice were infected at 0.9% and 8.9% parasitemia, respectively. Albitiazolium that had accumulated in infected erythrocytes and in the spleen was released into the plasma, where it was then available for another round of pharmacological activity. This recycling of the accumulated drug, after the rupture of the infected erythrocytes, likely extends its pharmacological effect. We also established a new viability assay in the P. vinckei-infected mouse model to discriminate between fast-and slow-acting antimalarials. We found that albitiazolium impaired parasite viability in less than 6 and 3 h at the ring and late stages, respectively, while parasite morphology was affected more belatedly. This highlights that viability and morphology are two parameters that can be differentially affected by a drug treatment, an element that should be taken into account when screening new antimalarial drugs.

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“…Com base nisso, propomos que os inibidores possam se acumular rapidamente dentro da célula hospedeira, promovendo a inibição da invasão. Essa característica físico-química tem sido reportada aos sais de bistiazólio aplicados contra Plasmodium falciparum, nos quais também foram capazes de se acumular dentro da célula hospedeira, promovendo sua atividade antimalárica[99]. de diferentes tipos celulares[36].…”

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Planejamento molecular, atividade tripanossomicida e anticancerígena de inibidores covalentes reversíveis de cisteíno proteases

Junior¹,

Carlos²

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Cysteine proteases (CP) activity has been related to different pathologies, such as leishmaniasis, Chagas disease and some types of cancer. Due to the homology between cysteine proteases expressed by these cellular systems, it was investigated here the importance of these enzymes for the development and establishment of these diseases based on the in vitro biological activity of novel reversible cysteine protease inhibitors. In general, inhibitors had a significant inhibitory activity of cysteine proteases in all assays, with a maximum inhibition of 42 % for Neq0554 concerning the CP activity expressed by Leishmania spp. and 76 % to CP activity expressed by pancreatic cancer cells. Different profiles of biological activity were observed between the cellular systems, but all substances had significant CP activity suppression, in cytostatic levels after the inhibition of CPA. When the inhibitors were tested against Leishmania spp., the cell growth was suppressed by at least 67 %, with maximum inhibition of 95% for Neq0551 at 10 μM. Similarly in pancreatic cancer cells, changes in the cell cycle profile were the most evident results, as well as the suppression of migration and colony formation ability, with 50 % retention of the colony development of MiaPaCa-2 cells by Neq0554 at 10 μM. In contrast, to protozoa from Trypanosoma cruzi Y strain, the inhibitors tested showed an interesting selectivity against the parasites concerning the host cell LLC-MK2, also promoting the in vitro cell invasion suppression in about 80% when the host cell was pre-treated with Neq0662 10 μM for 2 h. Finally, the encapsulation of Neq0554 promoted an increase in its anticancer activity against pancreatic cancer cells, with IC 50 of 79 μM alongside > 200 μM to fibroblast cells, besides increasing its selectivity. In general, the results corroborate the hypothesis that the inhibition of cysteine proteases in the cellular systems is efficient to promote cytostatic effects, being an interesting tool to be used as control and development suppression of some pathologies. Also, CP activity in protozoa cells and pancreatic cancer showed a similar profile of action, in which cysteine protease inhibitors did not promote death at a significant level for the cells, but emphasized cytostatic effects about cell growth.

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New Insight into the Mechanism of Accumulation and Intraerythrocytic Compartmentation of Albitiazolium, a New Type of Antimalarial

Cited by 10 publications

References 43 publications

Identification of Antimalarial Compounds That Require CLAG3 for Their Uptake by Plasmodium falciparum -Infected Erythrocytes

Identification of Antimalarial Compounds That Require CLAG3 for Their Uptake by Plasmodium falciparum -Infected Erythrocytes

High Accumulation and In Vivo Recycling of the New Antimalarial Albitiazolium Lead to Rapid Parasite Death

Planejamento molecular, atividade tripanossomicida e anticancerígena de inibidores covalentes reversíveis de cisteíno proteases

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