Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.494
Filtrar
2.
Parasit Vectors ; 14(1): 36, 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33422141

RESUMO

BACKGROUND: Zoonotic visceral leishmaniasis by Leishmania infantum is a first-order pathology in canine veterinary clinics in endemic areas. Moreover, canine infections are considered the main reservoir for human disease; despite their importance in the control of the disease within a One Health approach, no scientometric study has been published. Aims of the study included analyzing the impact of canine leishmaniasis (CanL) on the scientific literature, drugs or combinations used, trends in the period from 2000 to 2020 and efficacy criteria employed. METHODS: A Web of Science (WOS)-based analysis of publications on CanL and chemotherapy of the disease in the period 2000-2020 was carried out using a stepwise methodology. Data were analyzed by year, geographical origin, chemical groups, drugs and combinations, and efficacy criteria. RESULTS: Reports on CanL (n = 3324) represented < 16% of all publications on leishmaniasis (n = 20,968), and of these around 18% (n = 596) were related to chemotherapy. Publication records on CanL followed the distribution of the infection by L. infantum in endemic areas although Mediterranean countries were overrepresented in the reports on chemotherapy of CanL. Publications on the main antileishmanial drugs used in clinical practice showed a sustained tendency in the period analyzed. Pentavalent antimonials (SbV), alone or in combination with allopurinol, represented > 50% of all publications on chemotherapy of CanL despite the availability of more recently marketed drugs. CONCLUSIONS: Chemotherapy of CanL still relies on SbV and combinations and to a lesser extent on miltefosine (MIL). Reports on chemotherapy are scarce and mostly publicly funded, and the variability of experimental conditions hampers the direct comparison of the efficacy of drugs, combinations and schedules. The vast majority of reports on efficacy do not include any information on supportive therapy; this reduces the actual value of the studies if intended for the practical management of the disease. Complete reports on the chemotherapy (etiological + symptomatic) would add value to the trials performed.


Assuntos
Antiprotozoários/uso terapêutico , Doenças do Cão/tratamento farmacológico , Tratamento Farmacológico/métodos , Leishmaniose/tratamento farmacológico , Alopurinol/uso terapêutico , Anfotericina B/uso terapêutico , Animais , Doenças do Cão/epidemiologia , Cães , Combinação de Medicamentos , Humanos , Leishmania infantum , Leishmaniose/epidemiologia , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/terapia , Fosforilcolina/análogos & derivados , Publicações
4.
Parasitol Res ; 119(9): 2943-2954, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32607710

RESUMO

Trypanosomatidae is a family of unicellular parasites belonging to the phylum Euglenozoa, which are causative agents in high impact human diseases such as Leishmaniasis, Chagas disease and African sleeping sickness. The impact on human health and local economies, together with a lack of satisfactory chemotherapeutic treatments and effective vaccines, justifies stringent research efforts to search for new disease therapies. Here, we present in vitro trypanocidal activity data and mode of action data, repositioning leishmanicidal [1,2,3]Triazolo[1,5-a]pyridinium salts against Trypanosoma cruzi, the aetiological agent of Chagas disease. This disease is one of the most neglected tropical diseases and is a major public health issue in Central and South America. The disease affects approximately 6-7 million people and is widespread due to increased migratory movements. We screened a suite of leishmanicidal [1,2,3]Triazolo[1,5-a]pyridinium salt compounds, of which compounds 13, 20 and 21 were identified as trypanocidal drugs. These compounds caused cell death in a mitochondrion-dependent manner through a bioenergetic collapse. Moreover, compounds 13 and 20 showed a remarkable inhibition of iron superoxide dismutase activity of T. cruzi, a key enzyme in the protection from the damage produced by oxidative stress.


Assuntos
Doença de Chagas/tratamento farmacológico , Compostos de Piridínio/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Reposicionamento de Medicamentos , Humanos , Leishmaniose/tratamento farmacológico , Membranas Mitocondriais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , América do Sul , Superóxido Dismutase/metabolismo , Tripanossomíase Africana/tratamento farmacológico
5.
Exp Parasitol ; 216: 107940, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32562606

RESUMO

Therapeutic options for the treatment of leishmaniasis are insufficient and need improvements owing to their low efficiency and high toxicity as well as the emergence of resistant strains. The limited number of new drugs for neglected diseases and lack of innovation in your development are still challenges. In this context, the process of discovery and development of biological assays play a pivotal role for the identification of bioactive compounds. The assays currently used for screening of drugs with cytotoxic activity against Leishmania parasites, include different processes that utilize intact parasite (free or intracellular) or specific enzymes of metabolism as a target cell. These assays allow the screening of large numbers of samples followed by more detailed secondary confirmatory assays to confirm the observed activity and assess their toxicity. In the present study, we described the development of a new functional and more complete assay that enables simultaneous assessment of potential anti-Leishmania compounds through evaluation of internalization of fluorescein-labeled L. braziliensis promastigotes by human peripheral blood monocytes and their cytotoxicity by flow cytometry. We standardized the conditions for parasite labeling to achieve better phagocytosis analysis by setting the ratio of number of parasites per cell as 1 to 2, at incubation time of 6h. The cytotoxicity assessment was performed by the quantification of cells undergoing early/late apoptosis and necrosis using a double labelling platform employing 7AAD for late apoptosis and necrosis analysis and Annexin-V for early apoptosis evaluation. Hemolysis analysis was an additional parameter to test cytotoxicity. Two drugs used on clinic (Amphotericin B and Glucantime®) were used to validate the proposed methodology, and the assay was able to detect their known leishmanicidal activity and immunotoxicity properties. This new predictive assay will contribute to the development of translational medicine strategies in drug discovery for neglected diseases such as leishmaniasis.


Assuntos
Alternativas aos Testes com Animais/métodos , Antiprotozoários/toxicidade , Citometria de Fluxo/métodos , Leishmania/efeitos dos fármacos , Doenças Negligenciadas/tratamento farmacológico , Adulto , Anfotericina B/farmacologia , Anfotericina B/toxicidade , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Fluoresceína-5-Isotiocianato , Corantes Fluorescentes , Humanos , Leishmania braziliensis/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Leucócitos/parasitologia , Antimoniato de Meglumina/farmacologia , Antimoniato de Meglumina/uso terapêutico , Antimoniato de Meglumina/toxicidade , Microscopia Confocal , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/parasitologia , Fatores de Tempo , Adulto Jovem
6.
Parasitol Res ; 119(7): 2025-2037, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32504119

RESUMO

Leishmaniasis is a neglected tropical disease with no effective vaccines to date. Globally, it affects around 14 million people living in undeveloped and developing countries. Leishmania, which is the causative eukaryotic organism, possesses unique enzymes and pathways that deviates from its mammalian hosts. The control strategy against leishmaniasis currently depends on chemotherapeutic methods. But these chemotherapeutic therapies possess several side effects, and therefore, the identification of potential drug targets has become very crucial. Identification of suitable drug targets is necessary to design specific inhibitors that can target and control the parasite. These unique enzymes can be used as possible drug targets after biochemical characterization and understanding the role of these enzymes. In this review, the authors discuss various metabolic pathways that are essential for the survival of the parasite and can be exploited as potential drug targets against leishmaniasis.


Assuntos
Antiparasitários , Leishmania/metabolismo , Leishmaniose/tratamento farmacológico , Redes e Vias Metabólicas/efeitos dos fármacos , Terapia de Alvo Molecular , Animais , Antiparasitários/farmacologia , Antiparasitários/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Leishmania/efeitos dos fármacos
7.
J Nat Med ; 74(3): 606-611, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32277328

RESUMO

Six limonoids [kotschyienone A and B (1, 2), 7-deacetylgedunin (3), 7-deacetyl-7-oxogedunin (4), andirobin (5) and methyl angolensate (6)] were investigated for their trypanocidal and leishmanicidal activities using bloodstream forms of Trypanosoma brucei and promastigotes of Leishmania major. Whereas all compounds showed anti-trypanosomal activity, only compounds 1-4 displayed anti-leishmanial activity. The 50% growth inhibition (GI50) values for the trypanocidal and leishmanicidal activity of the compounds ranged between 2.5 and 14.9 µM. Kotschyienone A (1) was found to be the most active compound with a minimal inhibition concentration (MIC) value of 10 µM and GI50 values between 2.5 and 2.9 µM. Only compounds 1 and 3 showed moderate cytotoxicity against HL-60 cells with MIC and GI50 values of 100 µM and 31.5-46.2 µM, respectively. Compound 1 was also found to show activity against intracellular amastigotes of L. major with a GI50 value of 1.5 µM. The results suggest that limonoids have potential as drug candidates for the development of new treatments against trypanosomiasis and leishmaniasis.


Assuntos
Leishmania major/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Limoninas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase/tratamento farmacológico , Animais , Células HL-60 , Humanos , Testes de Sensibilidade Microbiana
8.
J Immunol ; 204(7): 1869-1880, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32132181

RESUMO

Leishmaniases are neglected tropical diseases. The treatment of leishmaniasis relies exclusively on chemotherapy including amphotericin B (AmB), miltefosine (hexadecylphosphocholine), and pentamidine. Besides the fact that these molecules are harmful for patients, little is known about the impact of such antileishmanial drugs on primary human cells in relation to immune function. The present study demonstrates that all antileishmanial drugs inhibit CD4 and CD8 T cell proliferation at the doses that are not related to increased cell death. Our results highlight that antileishmanial drugs have an impact on monocytes by altering the expression of IL-12 induced by LPS, whereas only AmB induced IL-10 secretion; both cytokines are essential in regulating Th1 cell-mediated immunity. Interestingly, IL-12 and anti-IL-10 Abs improved T cell proliferation inhibited by AmB. Furthermore, our results show that in contrast to hexadecylphosphocholine and pentamidine, AmB induced gene expression of the inflammasome pathway. Thus, AmB induced IL-1ß and IL-18 secretions, which are reduced by specific inhibitors of caspase activation (Q-VD) and NLRP3 activation (MCC950). Our results reveal previously underestimated effects of antileishmanial drugs on primary human cells.


Assuntos
Antiparasitários/farmacologia , Inflamassomos/efeitos dos fármacos , Interleucina-12/metabolismo , Leishmania/genética , Leishmaniose/tratamento farmacológico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-10/metabolismo , Leishmania/metabolismo , Leishmaniose/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Parasite Immunol ; 42(6): e12713, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32173875

RESUMO

Canine leishmaniasis (CanL) is caused by the intracellular parasite Leishmania infantum. Prostaglandin E2 (PGE2 ) exerts potent regulatory effects on the immune system in experimental model Leishmania infection, but this influence has not yet been studied in CanL. In this study, PGE2 and PGE2 receptor levels and the regulatory effect of PGE2 on arginase activity, NO2 , IL-10, IL-17, IFN-γ, TNF-α and parasite load were evaluated in cultures of splenic leucocytes obtained from dogs with CanL in the presence of agonists and inhibitors. Our results showed that splenic leucocytes from dogs with CanL had lower EP2 receptor levels than those of splenic leucocytes from healthy animals. We observed that NO2 levels decreased when the cells were treated with a PGE2 receptor agonist (EP1/EP2/EP3) or COX-2 inhibitor (NS-398) and that TNF-α, IL-17 and IFN-γ cytokine levels decreased when the cells were treated with a PGE2 receptor agonist (EP2) or PGE2 itself. The parasite load in splenic leucocyte cell cultures from dogs with CanL decreased after stimulation of the cells with PGE2 . We conclude that Leishmania infection of dogs modulates PGE2 receptors and speculate that the binding of PGE2 to its receptors may activate the microbicidal capacity of cells.


Assuntos
Citocinas/imunologia , Dinoprostona/metabolismo , Doenças do Cão/tratamento farmacológico , Leishmania infantum/imunologia , Leishmaniose/veterinária , Receptores de Prostaglandina E/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/agonistas , Dinoprostona/antagonistas & inibidores , Doenças do Cão/imunologia , Doenças do Cão/parasitologia , Cães , Leishmaniose/tratamento farmacológico , Leishmaniose/imunologia , Óxido Nítrico/análise , Nitrobenzenos/farmacologia , Carga Parasitária , Receptores de Prostaglandina E/agonistas , Receptores de Prostaglandina E/fisiologia , Sulfonamidas/farmacologia , Fator de Necrose Tumoral alfa/imunologia
10.
Rev Soc Bras Med Trop ; 53: e20180463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049198

RESUMO

INTRODUCTION: The therapeutic efficacy of daily amphotericin B infusion is related to its maximum concentration in blood; however, trough levels may be useful in intermittent regimens of this antifungal drug. METHODS: : High performance liquid chromatography (HPLC) was used to determine the minimum concentration (Cmin) of amphotericin B in the serum of patients receiving deoxycholate (D-Amph) or liposomal amphotericin B (L-AmB) for the treatment of cryptococcal meningitis (n=28), histoplasmosis (n=8), paracoccidioidomycosis (n=1), and leishmaniasis (n=1). RESULTS: Daily use of D-Amph 30 to 50 mg or L-AmB 50 mg resulted in a similar Cmin, but a significant increase ocurred with L-AmB 100 mg/day. The geometric mean Cmin tended to decrease with a reduction in the dose and frequency of intermittent L-AmB infusions: 357 ng/mL (100 mg 4 to 5 times/week) > 263 ng/mL (50 mg 4 to 5 times/week) > 227 ng/mL (50 mg 1 to 3 times/week). The impact on Cmin was variable in patients whose dose or therapeutic scheme was changed, especially when administered the intermittent infusion of amphotericin B. The mean Cmin for each L-AmB schedule of intermittent therapy was equal or higher than the minimum inhibitory concentration of amphotericin B against Cryptococcus isolates from 10/12 patients. The Cmin of amphotericin B in patients with cryptococcal meningitis was comparable between those that survived or died. CONCLUSIONS: By evaluating the Cmin of amphotericin B, we demonstrated the therapeutic potential of its intermittent use including in the consolidation phase of neurocryptococcosis treatment, despite the great variability in serum levels among patients.


Assuntos
Anfotericina B/sangue , Antifúngicos/sangue , Ácido Desoxicólico/sangue , Anfotericina B/administração & dosagem , Anfotericina B/farmacocinética , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Cromatografia Líquida de Alta Pressão , Ácido Desoxicólico/administração & dosagem , Ácido Desoxicólico/farmacocinética , Histoplasmose/tratamento farmacológico , Humanos , Leishmaniose/tratamento farmacológico , Meningite Criptocócica/tratamento farmacológico , Paracoccidioidomicose/tratamento farmacológico
11.
Molecules ; 25(3)2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31979089

RESUMO

A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC50 values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC50 value of 2.52 ± 0.65 µm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.


Assuntos
Antiprotozoários/química , Antiprotozoários/uso terapêutico , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/patogenicidade , Tetraoxanos/química , Tetraoxanos/uso terapêutico , Animais , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Camundongos , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Fosforilcolina/uso terapêutico
12.
Chem Biol Interact ; 315: 108899, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31738906

RESUMO

Parasitic diseases still represent serious public health problems, since the high and steady emergence of resistant strains is evident. Because parasitic infections are distributed predominantly in developing countries, less toxic, more efficient, safer and more accessible drugs have become desirable in the treatment of the infected population. This is the case of leishmaniasis, an infectious disease caused by a protozoan of the genus Leishmania sp., responsible for triggering pathological processes from the simplest to the most severe forms leading to high rates of morbidity and mortality throughout the world. In the search for new leishmanicidal drugs, the thiosemicarbazones and the indole fragments have been identified as promising structures for leishmanicidal activity. The present study proposes the synthesis and structural characterization of new indole-thiosemicarbazone derivatives (2a-j), in addition to performing in vitro evaluations through cytotoxicity assays using macrophages (J774) activity against forms of Leishmania infantum and Leishmania amazonensis promastigote as well as ultrastructural analyzes in promastigotes of L. infantum. Results show that the indole-thiosemicarbazone derivatives were obtained with yield values varying from 32.09 to 94.64%. In the evaluation of cytotoxicity, the indole-thiosemicarbazone compounds presented CC50 values between 53.23 and 357.97 µM. Concerning the evaluation against L. amazonensis promastigote forms, IC50 values ranged between 12.31 and  > 481.52 µM, while the activity against L. infantum promastigotes obtained IC50 values between 4.36 and 23.35 µM. The compounds 2d and 2i tested against L. infantum were the most promising in the series, as they showed the lowest IC50 values: 5.60 and 4.36 respectively. The parasites treated with the compounds 2d and 2i showed several structural alterations, such as shrinkage of the cell body, shortening and loss of the flagellum, intense mitochondrial swelling and vacuolization of the cytoplasm leading the parasite to cellular unviability. Therefore, the indole-thiosemicarbazone compounds are promising because they yield considerable synthesis, have low cytotoxicity to mammalian cells and act as leishmanicidal agents.


Assuntos
Antiprotozoários/farmacologia , Indóis/farmacologia , Leishmania infantum/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Tiossemicarbazonas/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Leishmaniose/parasitologia , Macrófagos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos
13.
Infect Immun ; 88(3)2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31818959

RESUMO

The immune mechanisms that contribute to the efficacy of treatment of cutaneous leishmaniasis (CL) are not fully understood. The aim of this study was to define immune correlates of the outcome of treatment of CL caused by Leishmania (Viannia) species during standard of care treatment with pentavalent antimonials. We conducted a comparative expression profiling of immune response genes in peripheral blood mononuclear cells (PBMCs) and lesion biopsy specimens obtained from CL patients before and at the end of treatment (EoT) with meglumine antimoniate. The ex vivo response of PBMCs to L (V) panamensis partially reflected that of lesion microenvironments. Significant downregulation of gene expression profiles consistent with local innate immune responses (monocyte and neutrophil activation and chemoattractant molecules) was observed at EoT in biopsy specimens of patients who cured (n = 8), compared to those from patients with treatment failure (n = 8). Among differentially expressed genes, pretreatment expression of CCL2 was significantly predictive of the therapeutic response (receiver operating characteristic [ROC] curve, area under the curve [AUC] = 0.82, P = 0.02). Polymorphisms in regulatory regions of the CCL2 promoter were analyzed in a pilot cohort of DNA samples from CL patients (cures, n = 20, and treatment failure, n = 20), showing putative association of polymorphisms rs13900(C/T) and rs2857656(G/C) with treatment outcome. Our data indicate that dampening gene expression profiles of monocyte and neutrophil activation characterize clinical cure after treatment of CL, supporting participation of parasite-sustained inflammation or deregulated innate immune responses in treatment failure.


Assuntos
Antiprotozoários/uso terapêutico , Citocinas/metabolismo , Imunidade Inata/fisiologia , Leishmania/imunologia , Leishmaniose/tratamento farmacológico , Leishmaniose/imunologia , Antimoniato de Meglumina/uso terapêutico , Perfilação da Expressão Gênica , Humanos , Leishmaniose/metabolismo , Leucócitos Mononucleares/metabolismo , Proteínas Quimioatraentes de Monócitos/metabolismo , Monócitos/metabolismo
14.
Biochim Biophys Acta Gen Subj ; 1864(1): 129465, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676291

RESUMO

BACKGROUND: M20 aminopeptidases, such as Peptidase T (PepT), are implicated in the hydrolysis of oligopeptides during the terminal stages of protein degradation pathway to maintain turnover. Therefore, specific inhibition of PepT bores well for the development of novel next-generation antileishmanials. This work describes the metal dependence, substrate preferences and inhibition of PepT, and demonstrates in detail the role of its two conserved substrate binding residues. METHODS: PepT was purified and characterized using a scheme of peptide substrates and peptidomimetic inhibitors. Residues T364 and N378 were mutated and characterized with an array of biochemical, biophysical and structural biology methods. RESULTS: PepT sequence carries conserved motifs typical of M20 peptidases and our work on its biochemistry shows that this cytosolic enzyme carries broad substrate specificity with best cleavage preference for peptides carrying alanine at the P1 position. Peptidomimetics amastatin and actinonin occupied S1 pocket by competing with the substrate for binding to active site and inhibited PepT potently, while arphamenine A and bestatin were less effective inhibitors. We further show that the mutation of conserved substrate binding residues (T364 and N378) to alanine affects structure, reduces substrate binding and alters the amidolytic activity of this dimeric enzyme. CONCLUSIONS: PepT preferentially hydrolyzes oligopeptides carrying alanine at P1 position and is potently inhibited by peptidomimetics. Reduced substrate binding after mutations was a key factor involved in amidolytic digressions. GENERAL SIGNIFICANCE: This study provides insights for further exploration of the druggability of PepT and highlights prospective applications of this enzyme along with its mutazyme T364A/N378A.


Assuntos
Aminopeptidases/química , Leishmaniose/tratamento farmacológico , Oligopeptídeos/farmacologia , Peptidomiméticos/química , Sequência de Aminoácidos , Aminopeptidases/antagonistas & inibidores , Aminopeptidases/genética , Sítios de Ligação/efeitos dos fármacos , Humanos , Hidrólise/efeitos dos fármacos , Cinética , Leishmania/efeitos dos fármacos , Leishmania/enzimologia , Leishmania/patogenicidade , Leishmaniose/genética , Leishmaniose/parasitologia , Mutação/genética , Oligopeptídeos/química , Peptídeos/química , Peptídeos/farmacologia , Peptidomiméticos/farmacologia , Proteólise/efeitos dos fármacos , Especificidade por Substrato
15.
Amino Acids ; 52(2): 247-259, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31037461

RESUMO

Leishmania protozoans are the causative agent of leishmaniasis, a neglected tropical disease consisting of three major clinical forms: visceral leishmaniasis (VL), cutaneous leishmaniasis, and mucocutaneous leishmaniasis. VL is caused by Leishmania donovani in East Africa and the Indian subcontinent and by Leishmania infantum in Europe, North Africa, and Latin America, and causes an estimated 60,000 deaths per year. Trypanothione reductase (TR) is considered to be one of the best targets to find new drugs against leishmaniasis. This enzyme is fundamental for parasite survival in the human host since it reduces trypanothione, a molecule used by the tryparedoxin/tryparedoxin peroxidase system of Leishmania to neutralize the hydrogen peroxide produced by host macrophages during infection. Recently, we solved the X-ray structure of TR in complex with the diaryl sulfide compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine), which impairs the parasite defense against the reactive oxygen species by inhibiting TR with high efficiency. The compound binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding. On the basis of the RDS 777-TR complex, we synthesized structurally related diaryl sulfide analogs as TR inhibitors able to compete for trypanothione binding to the enzyme and to kill the promastigote in the micromolar range. One of the most active among these compounds (RDS 562) was able to reduce the trypanothione concentration in cell of about 33% via TR inhibition. RDS 562 inhibits selectively Leishmania TR, while it does not inhibit the human homolog glutathione reductase.


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Leishmania infantum/efeitos dos fármacos , Sulfetos/química , Sulfetos/farmacologia , Motivos de Aminoácidos , Domínio Catalítico , Glutationa/análogos & derivados , Glutationa/metabolismo , Humanos , Leishmania infantum/enzimologia , Leishmania infantum/metabolismo , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Modelos Moleculares , NADH NADPH Oxirredutases/antagonistas & inibidores , NADH NADPH Oxirredutases/química , NADH NADPH Oxirredutases/genética , NADH NADPH Oxirredutases/metabolismo , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Espermidina/análogos & derivados , Espermidina/metabolismo
16.
Curr Med Chem ; 27(5): 697-718, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30378482

RESUMO

Leishmaniasis and trypanosomiasis occur primarily in undeveloped countries and account for millions of deaths and disability-adjusted life years. Limited therapeutic options, high toxicity of chemotherapeutic drugs and the emergence of drug resistance associated with these diseases demand urgent development of novel therapeutic agents for the treatment of these dreadful diseases. In the last decades, different in silico methods have been successfully implemented for supporting the lengthy and expensive drug discovery process. In the current review, we discuss recent advances pertaining to in silico analyses towards lead identification, lead modification and target identification of antileishmaniasis and anti-trypanosomiasis agents. We describe recent applications of some important in silico approaches, such as 2D-QSAR, 3D-QSAR, pharmacophore mapping, molecular docking, and so forth, with the aim of understanding the utility of these techniques for the design of novel therapeutic anti-parasitic agents. This review focuses on: (a) advanced computational drug design options; (b) diverse methodologies - e.g.: use of machine learning tools, software solutions, and web-platforms; (c) recent applications and advances in the last five years; (d) experimental validations of in silico predictions; (e) virtual screening tools; and (f) rationale or justification for the selection of these in silico methods.


Assuntos
Leishmaniose , Tripanossomíase , Simulação por Computador , Desenho de Fármacos , Humanos , Leishmaniose/tratamento farmacológico , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Tripanossomíase/tratamento farmacológico
17.
Parasite ; 26: 71, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31825305

RESUMO

Leishmaniases still represent a global scourge and new therapeutic tools are necessary to replace the current expensive, difficult to administer treatments that induce numerous adverse effects and for which resistance is increasingly worrying. In this context, the particularly original organization of the Leishmania parasite in comparison to higher eukaryotes is a great advantage. It allows for the development of new, very specific, and thus non-cytotoxic treatments. Among these originalities, Leishmania cell death can be cited. Despite a classic pattern of apoptosis, key mammalian apoptotic proteins are not present in Leishmania, such as caspases, cell death receptors, and anti-apoptotic molecules. Recent studies have helped to develop a better understanding of parasite cell death, identifying new proteins or even new apoptotic pathways. This review provides an overview of the current knowledge on Leishmania cell death, describing its physiological roles and its phenotype, and discusses the involvement of various proteins: endonuclease G, metacaspase, aquaporin Li-BH3AQP, calpains, cysteine proteinase C, LmjHYD36 and Lmj.22.0600. From these data, potential apoptotic pathways are suggested. This review also offers tools to identify new Leishmania cell death effectors. Lastly, different approaches to use this knowledge for the development of new therapeutic tools are suggested: either inhibition of Leishmania cell death or activation of cell death for instance by treating cells with proteins or peptides involved in parasite death fused to a cell permeant peptide or encapsulated into a lipidic vector to target intra-macrophagic Leishmania cells.


Assuntos
Morte Celular , Leishmania/fisiologia , Animais , Apoptose , Humanos , Leishmania/efeitos dos fármacos , Leishmania/enzimologia , Leishmaniose/tratamento farmacológico , Redes e Vias Metabólicas/efeitos dos fármacos , Fenótipo , Psychodidae/parasitologia
18.
Top Companion Anim Med ; 37: 100356, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31837752

RESUMO

We report an unusual case of leishmaniosis with the involvement of mammary glands in an old cat with what seems to be a concurrent regressive feline leukemia virus infection. Leishmania donovani complex parasites were identified for the first time in inflammatory breast fluid during a clinical recurrence manifested about 4 years after the first diagnosis of feline leishmaniosis. Combined treatment with allopurinol and meglumine antimoniate resulted in clinical cure of mammary lesion and a concurrent uveitis.


Assuntos
Doenças do Gato/parasitologia , Leishmaniose/veterinária , Glândulas Mamárias Animais/parasitologia , Alopurinol/uso terapêutico , Animais , Antiprotozoários/uso terapêutico , Doenças do Gato/tratamento farmacológico , Doenças do Gato/virologia , Gatos , Feminino , Leishmania donovani/isolamento & purificação , Leishmaniose/tratamento farmacológico , Vírus da Leucemia Felina , Leucemia Felina , Antimoniato de Meglumina/uso terapêutico , Portugal , Uveíte/tratamento farmacológico , Uveíte/veterinária
19.
Acta Biochim Biophys Sin (Shanghai) ; 51(12): 1286-1292, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31761925

RESUMO

Leishmaniasis, caused by the intracellular protozoan parasite Leishmania, remains an important neglected tropical infectious disease. Infection may be lethal if untreated. Currently, the available drugs for the disease are limited by high toxicity and drug resistance. There is an urgent need to develop novel anti-leishmanial strategies. Antimicrobial peptides (AMPs) have been described as the first-line immune defense against pathogenic microbes and are being developed as emerging anti-parasitic therapies. In the present study, we showed the anti-leishmanial activity of the synthetic 4-amino acid peptide lysine, aspartic acid, glutamic acid, and leucine (KDEL), the endoplasmic reticulum retention sequence, against Leishmania tarentolae promastigote and amastigote. Different concentrations of KDEL peptides were incubated with promastigotes, MTT viability assay, and promastigote assay were carried out. Macrophages infected with GFP-transfected L. tarentolae promastigotes were incubated with KDEL peptides, and the anti-amastigote activity of the KDEL peptides was measured by fluorescence microscopy. The damage of L. tarentolae was observed by light microscopy and electron microscopy. The cell apoptosis was analyzed using the Annexin V-FITC/PI apoptosis detection kit and mitochondrial membrane potential assay kit and by flow cytometry. Results showed that L. tarentolae was susceptible to KDEL peptides in a dose-dependent manner, and KDEL peptides disrupted the surface membrane integrity and caused cell apoptosis. In our study, we found for the first time an AMP KDEL from Pseudomonas aeruginosa and proved its significant therapeutic potential as a novel anti-leishmanial drug.


Assuntos
Anti-Infecciosos/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Peptídeos/farmacologia , Animais , Camundongos Endogâmicos BALB C , Pseudomonas aeruginosa/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...