P-type transport ATPases in<i>Leishmania</i>and<i>Trypanosoma</i>

Meade, John C.

doi:10.1051/parasite/2019069

Cited by 14 publications

(16 citation statements)

References 181 publications

(206 reference statements)

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“…This steroid is absent in mammalian counterparts, whereas cholesterol is the major counterpart of the mammalian cell membrane. Therefore, the sterol biosynthesis machinery of trypanosomatids is widely studied in drug discovery and drugs as the clinically used amphotericin B ( Leishmania parasites) targets the ergosterol [38] . Proper ionic balance is required for different cellular processes including maintaining of pH, osmolarity regulation and cell volume [39,40] .…”

Section: Resultsmentioning

confidence: 99%

Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates

Souza

Costa-Silva

Morais

et al. 2021

Chemistry & Biodiversity

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The search for the pharmacophore of a bioactive compound, crucial for drug discovery studies, involves the adequate arrangement of different atoms in the molecule. As part of a continuous work aiming discovery of new drug candidates against the protozoan parasite Trypanosoma cruzi, the hexane extract of Hydrocotyle bonariensis was subjected to a bioactivity‐guided fractionation to afford two chemically related dibenzylbutyrolactone lignans – hinokinin (1) and hibalactone (2). Compounds 1 and 2 showed activity against trypomastigote with EC50 values of 17.0 and 69.4 μM, respectively. Compound 1 was also active against the clinically relevant form of the parasite, amastigotes, displaying an EC50 value of 34.4 μM. The structure‐activity relationship (SAR) indicated that the absence of the double bond at C‐7 is a crucial feature for the increment of the antiparasitic activity. The lethal action of the most potent compound 1 was investigated in the trypomastigotes. The fluorescent‐based assay with SYTOX Green demonstrated a significant alteration of the plasma membrane permeability of the parasite. Additionally, compound 1 demonstrated no significant hemolytic activity in mice erythrocytes at 200 μM. To search the pharmacophore, three different simplified compounds – 3,4‐methylenedioxydihydrocinnamic acid (3), 3,4‐methylenedioxydihydrocinnamic alcohol (4) and 3,4‐methylenedioxycinnamic acid (5) – were prepared and tested against T. cruzi. These derivatives displayed EC50 values of 37.2 (3), 25.8 (4) and 73.5 (5) μM against trypomastigotes, and 41.3 (3) and 48.2 (4) μM against amastigotes, whereas compound 5 was inactive. Except for compound 2, which resulted in a CC50 value of 114.5 μM, all compounds showed no mammalian cytotoxicity at 200 μM. An in silico ADMET study was performed and predicted values demonstrated an acceptable drug‐likeness profile for compounds 1–5. Despite the minor reduction in the potency, the simplified derivatives retained the antitrypanosomal activity against the intracellular amastigotes, even with 95 % reduction of their molecular weight. Additionally, in silico studies suggested them as more soluble compounds, making these simplified structures promising scaffolds for optimization studies in Chagas disease.

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Section: Resultsmentioning

confidence: 99%

Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates

Souza

Costa-Silva

Morais

et al. 2021

Chemistry & Biodiversity

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“…Though the Cytochrome C oxidase complex (that is known to bind copper) has been identified in Leishmania and its component Ldp27 has been shown to be crucial in amastigote survival, no information is available about role of copper in the secretory pathway [43]. Additionally, presence of a Cu/Zn-type superoxide dismutase in Leishmania glycosomes may indicate the role of a Copper P-type ATPase in incorporating copper to TGN and intracellular organelles [44]. Although the role of iron has been extensively studied in kinetoplastid parasites; there has been limited efforts to understand the role of copper in their survival or pathogenicity.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, presence of a Cu/Zn-type superoxide dismutase in Leishmania glycosomes may indicate the role of a Copper P-type ATPase in incorporating copper to TGN and intracellular organelles [44]. Although the role of iron has been extensively studied in kinetoplastid parasites; there has been limited efforts to understand the role of copper in their survival or pathogenicity.…”

Section: Discussionmentioning

confidence: 99%

The novel leishmanial Copper P-type ATPase plays a vital role in intracellular parasite survival

Paul

Banerjee

Sen

et al. 2021

Preprint

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Copper is essential for all life forms; however in excess it is extremely toxic. Toxic properties of copper are utilized by hosts against various pathogenic invasions. Leishmania, in its both free-living and intracellular forms was found to exhibit appreciable tolerance towards copper-stress. To determine the mechanism of copper-stress evasion employed by Leishmania we identified and characterized the hitherto unknown Copper-ATPase in Leishmania major and determined its role in parasite’s survival in host macrophage cells. L. major Cu-ATPase, LmATP7, exhibits high homology with its orthologues at multiple conserved motifs. In promastigotes, LmATP7 localized to the plasma membrane with a fraction in intracellular puncta. Upon copper treatment, LmATP7 expression increases few folds. LmATP7 is capable of complementing copper transport in Cu-ATPase-Δ yeast strain. Promastigotes overexpressing LmATP7 exhibits higher survival upon copper stress indicating efficacious copper export compared to wild type parasites. We explored macrophage-Leishmanial interaction with respect to copper stress subjected by the host upon parasite and the parasite’s reciprocating response thereon to evade the stress. The Copper-P-type-ATPases ATP7A/7B serves as major copper exporter in eukaryotes that maintain cellular copper levels. We found that Leishmania infection, triggers ATP7A upregulation in macrophages. Additionally, as part of host response, ATP7A traffics from trans-Golgi network and transports copper to the endosomal and endolysosomal compartments harbouring the Leishmania amastigotes. Finally, we show LmATP7 overexpression in this parasite, increased amastigote survivability within infected macrophages, establishing its role in combating host-induced copper stress.

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“…P-type ATPase expression has also been demonstrated in Trypanosoma brucei brucei, where it is localized to subcellular vesicles and probably the cell membrane, although its detoxification function has not been confirmed ( Isah et al, 2020 ). In Trypanosoma cruzi, a probable copper-transporting ATPase is upregulated in the intracellular stage in host cells compared with the extracellular stage in the insect vector ( Meade, 2019 ). The intracellular stage has to survive in the phagosomal compartment with excessive copper levels, and the upregulation of copper translocating ATPase may indicate its role in detoxification.…”

Section: Introductionmentioning

confidence: 99%

Copper detoxification machinery of the brain-eating amoeba Naegleria fowleri involves copper-translocating ATPase and the antioxidant system

Grechnikova

Ženíšková

Malych

et al. 2020

International Journal for Parasitology: Drugs and Drug Resistan

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Copper is a trace metal that is necessary for all organisms but toxic when present in excess. Different mechanisms to avoid copper toxicity have been reported to date in pathogenic organisms such as Cryptococcus neoformans and Candida albicans . However, little if anything is known about pathogenic protozoans despite their importance in human and veterinary medicine. Naegleria fowleri is a free-living amoeba that occurs naturally in warm fresh water and can cause a rapid and deadly brain infection called primary amoebic meningoencephalitis (PAM). Here, we describe the mechanisms employed by N. fowleri to tolerate high copper concentrations, which include various strategies such as copper efflux mediated by a copper-translocating ATPase and upregulation of the expression of antioxidant enzymes and obscure hemerythrin-like and protoglobin-like proteins. The combination of different mechanisms efficiently protects the cell and ensures its high copper tolerance, which can be advantageous both in the natural environment and in the host. Nevertheless, we demonstrate that copper ionophores are potent antiamoebic agents; thus, copper metabolism may be considered a therapeutic target.

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P-type transport ATPases inLeishmaniaandTrypanosoma

Cited by 14 publications

References 181 publications

Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates

Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates

The novel leishmanial Copper P-type ATPase plays a vital role in intracellular parasite survival

Copper detoxification machinery of the brain-eating amoeba Naegleria fowleri involves copper-translocating ATPase and the antioxidant system

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