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1.
Parasitol Res ; 119(2): 649-657, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31897791

RESUMO

Leishmania donovani is the causative agent of visceral leishmaniasis. Annually, 500 million new cases of infection are reported mainly in poor communities, decreasing the interest of the pharmaceutical industries. Therefore, the repositioning of new drugs is an ideal strategy to fight against these parasites. SQ109, a compound in phase IIb/III of clinical trials to treat resistant Mycobacterium tuberculosis, has a potent effect against Trypanosoma cruzi, responsible for Chagas' disease, and on Leishmania mexicana, the causative agent of cutaneous and muco-cutaneous leishmaniasis. In the latter, the toxic dose against intramacrophagic amastigotes is very low (IC50 ~ 11 nM). The proposed mechanism of action on L. mexicana involves the disruption of the parasite intracellular Ca2+ homeostasis through the collapse of the mitochondrial electrochemical potential (ΔΨm). In the present work, we show a potent effect of SQ109 on L. donovani, the parasite responsible for visceral leishmaniasis, the more severe and uniquely lethal form of these infections, obtaining a toxic effect on amastigotes inside macrophages even lower to that obtained in L. mexicana (IC50 of 7.17 ± 0.09 nM) and with a selectivity index > 800, even higher than in L. mexicana. We also demonstrated for first time that SQ109, besides collapsing ΔΨm of the parasite, induced a very rapid damage to the parasite acidocalcisomes, essential organelles involved in the bioenergetics and many other important functions, including Ca2+ homeostasis. Both effects of the drug on these organelles generated a dramatic increase in the intracellular Ca2+ concentration, causing parasite death.


Assuntos
Adamantano/análogos & derivados , Etilenodiaminas/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Visceral/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Adamantano/farmacologia , Animais , Proliferação de Células , Doença de Chagas/tratamento farmacológico , Citoplasma , Humanos , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/parasitologia , Leishmaniose Visceral/parasitologia , Macrófagos/parasitologia , Mitocôndrias , Trypanosoma cruzi/efeitos dos fármacos
2.
FEBS J ; 286(19): 3909-3925, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31162791

RESUMO

Trypanosoma cruzi is the causative agent of Chagas disease. The only two drugs accepted for the treatment of this infection are benznidazole and nifurtimox, which are of limited use in the predominant chronic phase. On the search for new drugs, the intracellular Ca2+ regulation has been postulated as a possible target, due to differences found between host cells and the parasite. The mechanisms involved in the intracellular Ca2+ regulation of T. cruzi have been partially elucidated. However, nothing is known about a putative channel responsible for the Ca2+ entry into this parasite. In contrast, in Leishmania spp., a closely related hemoflagelate, a sphingosine-activated plasma membrane Ca2+ channel has been recently described. The latter resembles the L-type voltage-gated Ca2+ channel present in humans, but with distinct characteristics. This channel is one of the main targets concerning the mechanism of action of miltefosine, the unique oral drug approved against leishmaniasis. In the present work, we describe for the first time, the electrophysiological characterization of a sphingosine-activated Ca2+ channel of T. cruzi by reconstituting plasma membrane vesicles into giant liposomes and patch clamp. This channel shares some characteristic as activation by Bay K8644 and inhibition by channel blockers such as nifedipine. However, the T. cruzi channel differs from the L-type VGCC in its activation by sphingosine and/or miltefosine. Albeit the conductance for each, Ba2+ , Ca2+ and Sr2+ was similar, the parasite channel appears not to be voltage dependent. A gene that presents homology in critical amino acids with its human ortholog Ca2+ channel was identified.


Assuntos
Canais de Cálcio/fisiologia , Esfingosina/fisiologia , Trypanosoma cruzi/fisiologia , Animais , Antiprotozoários/farmacologia , Cálcio/metabolismo , Canais de Cálcio/efeitos dos fármacos , Transporte de Íons , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia
3.
Parasitol Int ; 70: 112-117, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30794871

RESUMO

Leishmaniasis is a parasitic disease representing an important problem of public health. Visceral leishmaniasis, resulting from infection with Leishmania donovani, causes considerable mortality and morbidity in the poorest region of the word. At present there is no current effective treatment, since the approved, drugs are expensive and are not free of undesirable side effects. Therefore, there is a need for the identification of new drugs. In this context, the parasite Ca2+ regulatory mechanisms in which mitochondria and acidocalcisomes are involved have been postulated as important targets for several trypanocidal drugs. Thus, amiodarone and dronedarone, common human antiarrythmics, exert its known action on these parasites through the disruption of the intracellular Ca2+ homeostasis. AMIODER is a benzofuran derivate based on the structure of amiodarone that recently demonstrates a significant effect on Trypanosoma cruzi. We now report the effect of AMIODER on Leishmania donovani demonstrating that it inhibit the growth of promastigotes and also of amastigotes inside macrophages, the clinically relevant stage of the parasite, obtaining IC50 values significantly lower than those reported for T. cruzi. We also show that this compound disrupted Ca2+ homeostasis in L. donovani, through its action on two organelles involved in the intracellular Ca2+ regulation and on the bioenergetics of the parasite. AMIODER totally collapsed the electrochemical membrane potential of the unique giant mitochondrion and simultaneously induced the alkalinization of acidocalcisomes, driving together to a large increase in the intracellular Ca2+ concentration of the parasite as the main mechanism of action of this benzofurane derivative.


Assuntos
Amiodarona/farmacologia , Benzofuranos/farmacologia , Leishmania donovani/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Tripanossomicidas/farmacologia , Animais , Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular , Citoplasma/química , Citoplasma/parasitologia , Descoberta de Drogas , Homeostase , Concentração Inibidora 50 , Leishmania donovani/crescimento & desenvolvimento , Leishmania donovani/metabolismo , Leishmaniose Visceral/tratamento farmacológico , Macrófagos/parasitologia , Redes e Vias Metabólicas , Camundongos
4.
Exp Parasitol ; 189: 8-15, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29684665

RESUMO

Chagas disease is a neglected tropical affection caused by the protozoan parasite Trypanosoma cruzi. There is no current effective treatment since the only two available drugs have a limited efficacy and produce side effects. Thus, investigation efforts have been directed to the identification of new drug leads. In this context, Ca2+ regulating mechanisms have been postulated as targets for antiparasitic compounds, since they present paramount differences when compared to host cells. Amiodarone is an antiarrhythmic with demonstrated trypanocidal activity acting through the disruption of the parasite intracellular Ca2+ homeostasis. We now report the effect of a benzofuran derivative based on the structure of amiodarone on T. cruzi. This derivative was able to inhibit the growth of epimastigotes in culture and of amastigotes inside infected cells, the clinically relevant phase. We also show that this compound, similarly to amiodarone, disrupts Ca2+ homeostasis in T. cruzi epimastigotes, via two organelles involved in the intracellular Ca2+ regulation and the bioenergetics of the parasite. We demonstrate that the benzofuran derivative was able to totally collapse the membrane potential of the unique giant mitochondrion of the parasite and simultaneously produced the alkalinization of the acidocalcisomes. Both effects are evidenced by a large increase in the intracellular Ca2+ concentration of T. cruzi.


Assuntos
Benzofuranos/farmacologia , Doença de Chagas/tratamento farmacológico , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Amiodarona/análogos & derivados , Amiodarona/química , Amiodarona/farmacologia , Animais , Benzofuranos/química , Benzofuranos/uso terapêutico , Cálcio/metabolismo , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Dronedarona , Concentração Inibidora 50 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Oxirredutases/metabolismo , Tripanossomicidas/química , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/metabolismo , Células Vero
5.
Artigo em Inglês | MEDLINE | ID: mdl-29061745

RESUMO

Leishmania donovani is the causing agent of visceral leishmaniasis, a common infection that affects millions of people from the most underdeveloped countries. Miltefosine is the only oral drug to treat infections caused by L. donovani Nevertheless, its mechanism of action is not well understood. While miltefosine inhibits the synthesis of phosphatidylcholine and also affects the parasite mitochondrion, inhibiting the cytochrome c oxidase, it is to be expected that this potent drug also produces its effect through other targets. In this context, it has been reported that the disruption of the intracellular Ca2+ homeostasis represents an important object for the action of drugs in trypanosomatids. Recently, we have described a plasma membrane Ca2+ channel in Leishmania mexicana, which is similar to the L-type voltage-gated Ca2+ channel (VGCC) present in humans. Remarkably, the parasite Ca2+ channel is activated by sphingosine, while the L-type VGCC is not affected by this sphingolipid. In the present work we demonstrated that, similarly to sphingosine, miltefosine is able to activate the plasma membrane Ca2+ channel from L. donovani Interestingly, nifedipine, the classical antagonist of the human channel, was not able to fully block the parasite plasma membrane Ca2+ channel, indicating that the mechanism of interaction is not identical to that of sphingosine. In this work we also show that miltefosine is able to strongly affect the acidocalcisomes from L. donovani, inducing the rapid alkalinization of these important organelles. In conclusion, we demonstrate two new mechanisms of action of miltefosine in L. donovani, both related to disruption of parasite Ca2+ homeostasis.


Assuntos
Antiprotozoários/farmacologia , Agonistas dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Leishmania donovani/efeitos dos fármacos , Organelas/efeitos dos fármacos , Organelas/metabolismo , Fosforilcolina/análogos & derivados , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Homeostase/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nifedipino/farmacologia , Fosforilcolina/farmacologia , Esfingosina/farmacologia
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