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1.
Front Cell Infect Microbiol ; 12: 824494, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35186797

RESUMO

Although macrophages have long been considered key players in the course of Leishmania infections, other non-professional phagocytes have lately been shown to maintain low levels of the parasite in safe intracellular niches. Recently, it was demonstrated that the adipose tissue is capable of harboring Old World L. (L.) infantum in mice. However, there is no evidence of experimental adipocyte infection with New World Leishmania species so far. In addition, it was not known whether adipocytes would be permissive for formation of the unique, large and communal parasitophorous vacuoles that are typical of L. (L.) amazonensis in macrophages. Here we evaluated the ability of L. (L.) amazonensis and L. (V.) braziliensis promastigotes and amastigotes to infect 3T3-L1 fibroblast-derived adipocytes (3T3-Ad) using light and transmission electron microscopy. Our results indicate that amastigotes and promastigotes of both species were capable of infecting and surviving inside pre- and fully differentiated 3T3-Ad for up to 144 h. Importantly, L. (L.) amazonensis amastigotes resided in large communal parasitophorous vacuoles in pre-adipocytes, which appeared to be compressed between large lipid droplets in mature adipocytes. In parallel, individual L. (V.) braziliensis amastigotes were detected in single vacuoles 144 h post-infection. We conclude that 3T3-Ad may constitute an environment that supports low loads of viable parasites perhaps contributing to parasite maintenance, since amastigotes of both species recovered from these cells differentiated into replicative promastigotes. Our findings shed light on the potential of a new host cell model that can be relevant to the persistence of New World Leishmania species.


Assuntos
Leishmania , Leishmaniose Cutânea , Leishmaniose , Células 3T3-L1 , Adipócitos , Animais , Leishmaniose/parasitologia , Camundongos , Camundongos Endogâmicos BALB C
2.
J Inorg Biochem ; 229: 111726, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35065320

RESUMO

Leishmania amazonensis and L. braziliensis are the main etiological agents of the American Tegumentary Leishmaniasis (ATL). Taking into account the limited effectiveness and high toxicity of the current drug arsenal to treat ATL, novel options are urgently needed. Inspired by the fact that gold-based compounds are promising candidates for antileishmanial drugs, we studied the biological action of a systematic series of six (1)-(6) symmetric Au(I) benzyl and aryl-N-heterocyclic carbenes. All compounds were active at low micromolar concentrations with 50% effective concentrations ranging from 1.57 to 8.30 µM against Leishmania promastigotes. The mesityl derivative (3) proved to be the best candidate from this series, with a selectivity index ~13 against both species. The results suggest an effect of the steric and electronic parameters of the N-substituent in the activity. Intracellular infections were drastically reduced after 24h of (2)-(5) incubation in terms of infection rate and amastigote burden. Further investigations showed that our compounds induced significant parasites' morphological alterations and membrane permeability. Also, (3) and (6) were able to reduce the residual activity of three Leishmania recombinant cysteine proteases, known as possible targets for Au(I) complexes. Our promising results open the possibility of exploring gold complexes as leishmanicidal molecules to be further screened in in vivo models of infection.


Assuntos
Imidazóis/farmacologia , Compostos Organoáuricos/farmacologia , Tripanossomicidas/farmacologia , Animais , Membrana Celular/efeitos dos fármacos , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Feminino , Ouro/química , Imidazóis/síntese química , Leishmania braziliensis/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Compostos Organoáuricos/síntese química , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química
3.
Trends Parasitol ; 37(8): 694-697, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34059455

RESUMO

Here we highlight coinfections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with ectoparasites, helminths, and protozoa, described in the literature, and the urgent need to understand the conditions of these associated pathologies. We emphasize the notion that such information is crucial for the continuity of measures that have been used for decades to control neglected parasitic diseases.


Assuntos
COVID-19 , Coinfecção , Doenças Parasitárias , Humanos , Doenças Negligenciadas/prevenção & controle , Doenças Parasitárias/prevenção & controle , SARS-CoV-2
4.
Bioorg Chem ; 114: 105041, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34130109

RESUMO

Cationic peptides bio-inspired by natural toxins have been recognized as an efficient strategy for the treatment of different health problems. Due to the specific interaction with substrates from biological membranes, snake venom phospholipases (PLA2s) represent valuable scaffolds for the research and development of short peptides targeting parasites, bacteria, and cancer cells. Considering this, we evaluated the in vitro therapeutic potential of three biomimetic peptides (pCergo, pBmTxJ and pBmje) based on three different amino acid sequences from Asp49 PLA2s. First, short amino acid sequences (12-17 in length) derived from these membranolytic toxins were selected using a combination of bioinformatics tools, including AntiCP, AMPA, PepDraw, ToxinPred, and HemoPI. The peptide, from each polypeptide sequence, with the greatest average antimicrobial index, no toxicity, and no hemolysis predicted was synthesized, purified, and characterized. According to in vitro assays performed, pBmje showed moderate cytotoxicity specifically against MCF-7 (breast cancer cells) with an EC50 of 464.85 µM, whereas pBmTxJ showed an antimicrobial effect against Staphylococcus aureus (ATCC 25923) with an MIC of 37.5 µM, and pCergo against E. coli (ATCC 25922) with an MIC of 75 µM. In addition, pCergo showed antileishmanial activity with an EC50 of 93.69 µM and 110.40 µM against promastigotes of Leishmania braziliensis and L. amazonensis, respectively. Altogether, these results confirmed the versatility of PLA2-derived synthetic peptides, highlighting the relevance of the use of these membrane-interacting toxins as specific archetypes for drug design focused on public health problems.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Fragmentos de Peptídeos/farmacologia , Fosfolipases A2/farmacologia , Tripanossomicidas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Biologia Computacional , Escherichia coli/efeitos dos fármacos , Feminino , Humanos , Leishmania/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/toxicidade , Fosfolipases A2/síntese química , Fosfolipases A2/toxicidade , Staphylococcus aureus/efeitos dos fármacos , Tripanossomicidas/síntese química , Tripanossomicidas/toxicidade
5.
ChemMedChem ; 16(11): 1681-1695, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33615725

RESUMO

Leishmaniasis is one of the most neglected diseases worldwide and is considered a serious public health issue. The current therapeutic options have several disadvantages that make the search for new therapeutics urgent. Gold compounds are emerging as promising candidates based on encouraging in vitro and limited in vivo results for several AuI and AuIII complexes. The antiparasitic mechanisms of these molecules remain only partially understood. However, a few studies have proposed the trypanothione redox system as a target, similar to the mammalian thioredoxin system, pointed out as the main target for several gold compounds with significant antitumor activity. In this review, we present the current status of the investigation and design of gold compounds directed at treating leishmaniasis. In addition, we explore potential targets in Leishmania parasites beyond the trypanothione system, taking into account previous studies and structure modulation performed for gold-based compounds.


Assuntos
Antiprotozoários/farmacologia , Descoberta de Drogas , Glutationa/análogos & derivados , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Compostos Organoáuricos/farmacologia , Espermidina/análogos & derivados , Animais , Antiprotozoários/química , Glutationa/antagonistas & inibidores , Glutationa/metabolismo , Humanos , Leishmania/metabolismo , Leishmaniose/metabolismo , Compostos Organoáuricos/química , Oxirredução , Testes de Sensibilidade Parasitária , Espermidina/antagonistas & inibidores , Espermidina/metabolismo
6.
Parasitol Res ; 120(2): 705-713, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33415404

RESUMO

Leishmaniasis is one of the most neglected parasitic infections of the world and current therapeutic options show several limitations. In the search for more effective drugs, plant compounds represent a powerful natural source. Artemisinin is a sesquiterpene lactone extracted from Artemisia annua L. leaves, from which dihydroartemisinin (DQHS) and artesunic acid (AA)/artesunate are examples of active derivatives. These lactones have been applied successfully on malaria therapy for decades. Herein, we investigated the sensitivity of Leishmania braziliensis, one of the most prevalent Leishmania species that cause cutaneous manifestations in the New World, to artemisinin, DQHS, and AA. L. braziliensis promastigotes and the stage that is targeted for therapy, intracelular amastigotes, were more sensitive to DQHS, showing EC50 of 62.3 ± 1.8 and 8.9 ± 0.9 µM, respectively. Cytotoxicity assays showed that 50% of bone marrow-derived macrophages cultures were inhibited with 292.8 ± 3.8 µM of artemisinin, 236.2 ± 4.0 µM of DQHS, and 396.8 ± 6.7 µM of AA. The control of intracellular infection may not be essentially attributed to the production of nitric oxide. However, direct effects on mitochondrial bioenergetics and H2O2 production appear to be associated with the leishmanicidal effect of DQHS. Our data provide support for further studies of artemisinin and derivatives repositioning for experimental leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Artemisininas/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Animais , Metabolismo Energético/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Leishmania braziliensis/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Mitocôndrias/metabolismo , Succinatos/farmacologia
7.
Acta Trop ; 215: 105803, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33373585

RESUMO

Chagas disease is a neglected tropical disease strongly associated with low socioeconomic status, affecting nearly 8 million people - mainly Latin Americans. The current infection risk is based on acute case reports, most of which are typically associated with oral transmissions. In the semi-arid region of Northeastern Brazil, serious outbreaks of this transmission type have surged in the last years. One of those occurred in 2016 in the state of Rio Grande do Norte. Rural residents of four municipalities surrounding Marcelino Vieira ingested sugar cane juice - which was probably ground with Trypanosoma cruzi-infected insects. Eighteen cases of Chagas disease were confirmed serologically, with two deaths reported. Socioeconomic information, schooling of residents and the structure of peridomestic and domestic environments in the rural area of Marcelino Vieira, along with entomological indicators, were investigated to understand better the factors related to the outbreaks in this region. We found triatomines (mainly Triatoma brasiliensis) in 35% (24/67) of domiciliary units and all rocky outcrops inspected (n = 7). Overall, 25% (91/357) of examined T. brasiliensis were infected by T. cruzi in artificial ecotopes, with almost the same prevalence in the sylvatic environment (22%; 35/154). Among all ecotopes investigated, wood/tile/brick piles were the ones linked to high insect infestations and triatomine T. cruzi infection prevalence. Ninety-five percent of people interviewed recognized the triatomines and knew the classic route of transmission of disease - triatomine bite-dependent. However, only 7.5% admitted knowledge that Chagas disease can also be acquired orally - which poses a risk this transmission route currently recognized. Here, we highlight the physical proximity between humans and triatomine populations with high T. cruzi infection prevalence as an additional risk factor to oral/vector contaminations. In sum, residents have low income, low level of education, and/or a willful disregard for the routes of Chagas disease transmission (specifically oral transmission), a combination of factors that may have favored the Chagas disease outbreak. We here provide recommendations to avoid further outbreaks.


Assuntos
Doença de Chagas/transmissão , Surtos de Doenças , Animais , Brasil/epidemiologia , Doença de Chagas/epidemiologia , Entomologia , Humanos , Insetos Vetores , Prevalência , Fatores de Risco , Fatores Socioeconômicos
8.
Pathog Dis ; 78(6)2020 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-32926094

RESUMO

Screenings of natural products have significantly contributed to the discovery of novel leishmanicidal agents. In this study, three known cruzioseptins-antibacterial peptides from Cruziohyla calcarifer skin-were synthesized and evaluated against promastigotes and amastigotes stages of Leishmania (L.) amazonensis and L. (V.) braziliensis. EC50 ranged from 9.17 to 74.82 µM, being cruzioseptin-1 the most active and selective compound, with selectivity index > 10 for both promastigotes and amastigotes of L. (V.) braziliensis. In vitro infections incubated with cruzioseptins at 50 µM showed up to ∼86% reduction in the amastigote number. Cruzioseptins were able to destabilize the parasite's cell membrane, allowing the incorporation of a DNA-fluorescent dye. Our data also demonstrated that hydrophobicity and charge appear to be advantageous features for enhancing parasiticidal activity. Antimicrobial cruzioseptins are suitable candidates and alternative molecules that deserve further in vivo investigation focusing on the development of novel antileishmanial therapies.


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Peptídeos/química , Peptídeos/farmacologia , Anfíbios/metabolismo , Animais , Humanos , Leishmaniose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Pele/metabolismo
9.
ChemMedChem ; 15(22): 2146-2150, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-32830445

RESUMO

A series of mononuclear coordination or organometallic AuI /AuIII complexes (1-9) have been comparatively studied in vitro for their antileishmanial activity against promastigotes and amastigotes, the clinically relevant parasite form, of Leishmania amazonensis and Leishmania braziliensis. One of the cationic AuI bis-N-heterocyclic carbenes (3) has low EC50 values (ca. 4 µM) in promastigotes cells and no toxicity in host macrophages. Together with two other AuIII complexes (6 and 7), the compound is also extremely effective in intracellular amastigotes from L. amazonensis. Initial mechanistic studies include an evaluation of the gold complexes' effect on L. amazonensis' plasma membrane integrity.


Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Compostos Organoáuricos/farmacologia , Animais , Antiprotozoários/química , Células Cultivadas , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Compostos Organoáuricos/química , Testes de Sensibilidade Parasitária
10.
J Nat Prod ; 83(1): 55-65, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31895573

RESUMO

A new method of screening was developed to generate 770 organic and water-soluble fractions from extracts of nine species of marine sponges, from the growth media of 18 species of marine-derived fungi, and from the growth media of 13 species of endophytic fungi. The screening results indicated that water-soluble fractions displayed significant bioactivity in cytotoxic, antibiotic, anti-Leishmania, anti-Trypanosoma cruzi, and inhibition of proteasome assays. Purification of water-soluble fractions from the growth medium of Penicillium solitum IS1-A provided the new glutamic acid derivatives solitumine A (1), solitumine B (2), and solitumidines A-D (3-6). The structures of compounds 1-6 have been established by analysis of spectroscopic data, chemical derivatizations, and vibrational circular dichroism calculations. Although no biological activity could be observed for compounds 1-6, the new structures reported for 1-6 indicate that the investigation of water-soluble natural products represents a relevant strategy in finding new secondary metabolites.


Assuntos
Glutamatos/química , Regiões Antárticas , Fungos/química , Estrutura Molecular , Penicillium/química , Água
11.
Artigo em Inglês | MEDLINE | ID: mdl-31454702

RESUMO

Phospholipase A2 toxins present in snake venoms interact with biological membranes and serve as structural models for the design of small peptides with anticancer, antibacterial and antiparasitic properties. Oligoarginine peptides are capable of increasing cell membrane permeability (cell penetrating peptides), and for this reason are interesting delivery systems for compounds of pharmacological interest. Inspired by these two families of bioactive molecules, we have synthesized two 13-mer peptides as potential antileishmanial leads gaining insights into structural features useful for the future design of more potent peptides. The peptides included p-Acl, reproducing a natural segment of a Lys49 PLA2 from Agkistrodon contortrix laticinctus snake venom, and its p-AclR7 analogue where all seven lysine residues were replaced by arginines. Both peptides were active against promastigote and amastigote forms of Leishmania (L.) amazonensis and L. (L.) infantum, while displaying low cytotoxicity for primary murine macrophages. Spectrofluorimetric studies suggest that permeabilization of the parasite's cell membrane is the probable mechanism of action of these biomolecules. Relevantly, the engineered peptide p-AclR7 was more active in both life stages of Leishmania and induced higher rates of ethidium bromide incorporation than its native template p-Acl. Taken together, the results suggest that short peptides based on phospholipase toxins are potential scaffolds for development of antileishmanial candidates. Moreover, specific amino acid substitutions, such those herein employed, may enhance the antiparasitic action of these cationic peptides, encouraging their future biomedical applications.


Assuntos
Venenos de Crotalídeos/farmacologia , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Peptídeos/farmacologia , Fosfolipases A2/farmacologia , Agkistrodon/metabolismo , Animais , Células Cultivadas , Venenos de Crotalídeos/síntese química , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/síntese química
12.
Comput Struct Biotechnol J ; 17: 352-361, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949306

RESUMO

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania (NTD) endemic in 98 countries. Although some drugs are available, current treatments deal with issues such as toxicity, low efficacy, and emergence of resistance. Therefore, there is an urgent need to identify new targets for the development of new antileishmanial drugs. Protein kinases (PKs), which play an essential role in many biological processes, have become potential drug targets for many parasitic diseases. A refined bioinformatics pipeline was applied in order to define and compare the kinomes of L. infantum and L. braziliensis, species that cause cutaneous and visceral manifestations of leishmaniasis in the Americas, the latter being potentially fatal if untreated. Respectively, 224 and 221 PKs were identified in L. infantum and L. braziliensis overall. Almost all unclassified eukaryotic PKs were assigned to six of nine major kinase groups and, consequently, most have been classified into family and subfamily. Furthermore, revealing the kinomes for both Leishmania species allowed for the prioritization of potential drug targets that could be explored for discovering new drugs against leishmaniasis. Finally, we used a drug repurposing approach and prioritized seven approved drugs and investigational compounds to be experimentally tested against Leishmania. Trametinib and NMS-1286937 inhibited the growth of L. infantum and L. braziliensis promastigotes and amastigotes and therefore might be good candidates for the drug repurposing pipeline.

13.
Parasitol Res ; 118(5): 1685-1686, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30903346

RESUMO

The original published version of this article contains error in Tables 1 and 2. Correct tables are presented here.

14.
Parasitol Res ; 118(5): 1625-1631, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30798369

RESUMO

Schistosomiasis is a neglected tropical disease affecting 220 million people worldwide. Praziquantel has proven to be effective against this parasitic disease, though there are increasing concerns regarding tolerance/resistance that calls for new drugs. Repurposing already existing and well-known drugs has been a desirable approach since it reduces time, costs, and ethical concerns. The anti-cancer drug tamoxifen (TAM) has been used worldwide for several decades to treat and prevent breast cancer. Previous reports stated that TAM affects Schistosoma hormonal physiology; however, no controlled schistosomicidal in vivo assays have been conducted. In this work, we evaluated the effect of TAM on female and male Schistosoma mansoni morphology, motility, and egg production. We further assessed worm survival and egg production in S. mansoni-infected mice. TAM induced morphological alterations in male and female parasites, as well as in eggs in vitro. Furthermore, in our in vivo experiments, one single dose of intraperitoneal TAM citrate reduced the total worm burden by 73% and led to a decrease in the amount of eggs in feces and low percentages of immature eggs in the small intestine wall. Eggs obtained from TAM citrate-treated mice were reduced in size and presented hyper-vacuolated structures. Our results suggest that TAM may be repurposed as a therapeutic alternative against S. mansoni infections.


Assuntos
Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/uso terapêutico , Tamoxifeno/uso terapêutico , Animais , Modelos Animais de Doenças , Resistência a Medicamentos/fisiologia , Fezes/parasitologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Praziquantel/uso terapêutico , Esquistossomose mansoni/parasitologia
15.
Anticancer Agents Med Chem ; 19(3): 389-401, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30417795

RESUMO

BACKGROUND: BRN2 transcription factor is associated with the development of malignant melanoma. The cytotoxic activities and cell death mechanism against B16F10-Nex2 cells were determined with synthetic peptide R18H derived from the POU domain of the BRN2 transcription factor. OBJECTIVE: To determine the cell death mechanisms and in vivo activity of peptide R18H derived from the POU domain of the BRN2 transcription factor against B16F10-Nex2 cells. METHODS: Cell viability was determined by the MTT method. C57Bl/6 mice were challenged with B16F10-Nex2 cells and treated with R18H. To identify the type of cell death, we used TUNEL assay, Annexin V and PI, Hoechst, DHE, and determination of caspase activation and cytochrome c release. Transmission electron microscopy was performed to verify morphological alterations after peptide treatment. RESULTS: Peptide R18H displayed antitumor activity in the first hours of treatment and the EC50% was calculated for 2 and 24h, being 0.76 ± 0.045 mM and 0.559 ± 0.053 mM, respectively. After 24h apoptosis was evident, based on DNA degradation, chromatin condensation, increase of superoxide anion production, phosphatidylserine translocation, activation of caspases 3 and 8, and release of extracellular cytochrome c in B16F10-Nex2 cells. The peptide cytotoxic activity was not affected by necroptosis inhibitors and treated cells did not release LDH in the extracellular medium. Moreover, in vivo antitumor activity was observed following treatment with peptide R18H. CONCLUSION: Peptide R18H from BRN2 transcription factor induced apoptosis in B16F10-Nex2 and displayed antitumor activity in vivo.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Homeodomínio/química , Melanoma/tratamento farmacológico , Melanoma/patologia , Fatores do Domínio POU/química , Peptídeos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Relação Estrutura-Atividade
16.
Int J Parasitol Drugs Drug Resist ; 8(3): 475-487, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30399513

RESUMO

Previous work from our group showed that tamoxifen, an oral drug that has been in use for the treatment of breast cancer for over 40 years, is active both in vitro and in vivo against several species of Leishmania, the etiological agent of leishmaniasis. Using a combination of metabolic labeling with [3H]-sphingosine and myo-[3H]-inositol, alkaline hydrolysis, HPTLC fractionations and mass spectrometry analyses, we observed a perturbation in the metabolism of inositolphosphorylceramides (IPCs) and phosphatidylinositols (PIs) after treatment of L. amazonensis promastigotes with tamoxifen, with a significant reduction in the biosynthesis of the major IPCs (composed of d16:1/18:0-IPC, t16:0/C18:0-IPC, d18:1/18:0-IPC and t16:0/20:0-IPC) and PIs (sn-1-O-(C18:0)alkyl -2-O-(C18:1)acylglycerol-3-HPO4-inositol and sn-1-O-(C18:0)acyl-2-O-(C18:1)acylglycerol-3-HPO4-inositol) species. Substrate saturation kinetics of myo-inositol uptake analyses indicated that inhibition of inositol transport or availability were not the main reasons for the reduced biosynthesis of IPC and PI observed in tamoxifen treated parasites. An in vitro enzymatic assay was used to show that tamoxifen was able to inhibit the Leishmania IPC synthase with an IC50 value of 8.48 µM (95% CI 7.68-9.37), suggesting that this enzyme is most likely one of the targets for this compound in the parasites.


Assuntos
Vias Biossintéticas/efeitos dos fármacos , Glicoesfingolipídeos/biossíntese , Leishmania/efeitos dos fármacos , Tamoxifeno/farmacologia , Glicoesfingolipídeos/metabolismo , Hexosiltransferases/efeitos dos fármacos , Hexosiltransferases/metabolismo , Concentração Inibidora 50 , Inositol/metabolismo , Leishmania/fisiologia , Leishmania mexicana/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Fosfatidilinositóis/metabolismo
17.
Int J Parasitol Drugs Drug Resist ; 8(3): 430-439, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30293058

RESUMO

Tritryps diseases are devastating parasitic neglected infections caused by Leishmania spp., Trypanosoma cruzi and Trypanosoma brucei subspecies. Together, these parasites affect more than 30 million people worldwide and cause high mortality and morbidity. Leishmaniasis comprises a complex group of diseases with clinical manifestation ranging from cutaneous lesions to systemic visceral damage. Antimonials, the first-choice drugs used to treat leishmaniasis, lead to high toxicity and carry significant contraindications limiting its use. Drug-resistant parasite strains are also a matter for increasing concern, especially in areas with very limited resources. The current scenario calls for novel and/or improvement of existing therapeutics as key research priorities in the field. Although several studies have shown advances in drug discovery towards leishmaniasis in recent years, key knowledge gaps in drug discovery pipelines still need to be addressed. In this review we discuss not only scientific and non-scientific bottlenecks in drug development, but also the central role of public-private partnerships for a successful campaign for novel treatment options against this devastating disease.


Assuntos
Descoberta de Drogas/métodos , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/efeitos adversos , Antiprotozoários/uso terapêutico , Antiprotozoários/toxicidade , Doença de Chagas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/estatística & dados numéricos , Descoberta de Drogas/legislação & jurisprudência , Descoberta de Drogas/estatística & dados numéricos , Descoberta de Drogas/tendências , Humanos , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Parcerias Público-Privadas , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Trypanosomatina/efeitos dos fármacos
18.
J Nat Prod ; 81(1): 188-202, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29297684

RESUMO

The isolation and identification of a series of new pseudoceratidine (1) derivatives from the sponge Tedania brasiliensis enabled the evaluation of their antiparasitic activity against Plasmodium falciparum, Leishmania (Leishmania) amazonensis, Leishmania (Leishmania) infantum, and Trypanosoma cruzi, the causative agents of malaria, cutaneous leishmaniasis, visceral leishmaniasis, and Chagas disease, respectively. The new 3-debromopseudoceratidine (4), 20-debromopseudoceratidine (5), 4-bromopseudoceratidine (6), 19-bromopseudoceratidine (7), and 4,19-dibromopseudoceratidine (8) are reported. New tedamides A-D (9-12), with an unprecedented 4-bromo-4-methoxy-5-oxo-4,5-dihydro-1H-pyrrole-2-carboxamide moiety, are also described. Compounds 4 and 5, 6 and 7, 9 and 10, and 11 and 12 have been isolated as pairs of inseparable structural isomers differing in their sites of bromination or oxidation. Tedamides 9+10 and 11+12 were obtained as optically active pairs, indicating an enzymatic formation rather than an artifactual origin. N12-Acetylpseudoceratidine (2) and N12-formylpseudoceratidine (3) were obtained by derivatization of pseudoceratidine (1). The antiparasitic activity of pseudoceratidine (1) led us to synthesize 23 derivatives (16, 17, 20, 21, 23, 25, 27-29, 31, 33, 35, 38, 39, 42, 43, 46, 47, 50, and 51) with variations in the polyamine chain and aromatic moiety in sufficient amounts for biological evaluation in antiparasitic assays. The measured antimalarial activity of pseudoceratidine (1) and derivatives 4, 5, 16, 23, 25, 31, and 50 provided an initial SAR evaluation of these compounds as potential leads for antiparasitics against Leishmania amastigotes and against P. falciparum. The results obtained indicate that pseudoceratidine represents a promising scaffold for the development of new antimalarial drugs.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Antiparasitários/química , Antiparasitários/farmacologia , Poríferos/química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Antiprotozoários/química , Antiprotozoários/farmacologia , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade , Trypanosoma cruzi/efeitos dos fármacos
19.
Parasitology ; 145(4): 490-496, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28274283

RESUMO

The aims of the present work were to test the effect of tamoxifen administered topically and the therapeutic efficacy of tamoxifen and pentavalent antimonial combinations in an experimental model of cutaneous leishmaniasis. BALB/c mice infected with a luciferase expressing line of Leishmania amazonensis were treated with topical tamoxifen in two different formulations (ethanol or oil-free cream) as monotherapy or in co-administration with pentavalent antimonial. Treatment efficacy was evaluated by lesion size and parasite burden, quantified through luminescence, at the end of treatment and 4 weeks later. Topical tamoxifen, formulated in ethanol or as a cream, was shown to be effective. The interaction between tamoxifen and pentavalent antimonial was additive in vitro. Treatment with combined schemes containing tamoxifen and pentavalent antimonial was effective in reducing lesion size and parasite burden. Co-administration of tamoxifen and pentavalent antimonial was superior to monotherapy with antimonial.


Assuntos
Antiprotozoários/uso terapêutico , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina/uso terapêutico , Pele/efeitos dos fármacos , Tamoxifeno/uso terapêutico , Administração Tópica , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/efeitos adversos , Quimioterapia Combinada/efeitos adversos , Etanol/química , Feminino , Leishmania mexicana/enzimologia , Leishmania mexicana/genética , Leishmaniose Cutânea/parasitologia , Luciferases/genética , Luminescência , Antimoniato de Meglumina/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Pele/parasitologia , Creme para a Pele/administração & dosagem , Creme para a Pele/efeitos adversos , Creme para a Pele/uso terapêutico , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Tamoxifeno/química
20.
PLoS Negl Trop Dis ; 9(5): e0003804, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26001191

RESUMO

Leishmania spp. are trypanosomatid parasites that replicate intracellularly in macrophages, causing serious human morbidity and mortality throughout the world. Trypanosomatid protozoa cannot synthesize heme, so must acquire this essential cofactor from their environment. Earlier studies identified LHR1 as a Leishmania amazonensis transmembrane protein that mediates heme uptake. Null mutants of LHR1 are not viable and single knockout strains have reduced virulence, but very little is known about the properties of LHR1 directly associated with heme transport. Here, we use functional assays in Saccharomyces cerevisiae to show that specific tyrosine residues within the first three predicted transmembrane domains of LHR1 are required for efficient heme uptake. These tyrosines are unique to LHR1, consistent with the low similarity between LHR1 and its corresponding homologs in C. elegans and human. Substitution of these tyrosines in LHR1 resulted in varying degrees of heme transport inhibition, phenotypes that closely mirrored the impaired ability of L. amazonensis to replicate as intracellular amastigotes in macrophages and generate cutaneous lesions in mice. Taken together, our results imply that the mechanism for heme transport by LHR1 is distinctive and may have adapted to secure heme, a limiting cofactor, inside the host. Since LHR1 is significantly divergent from the human heme transporter HRG1, our findings lay the groundwork for selective targeting of LHR1 by small molecule antagonists.


Assuntos
Heme/metabolismo , Leishmania mexicana/patogenicidade , Proteínas de Protozoários/metabolismo , Tirosina , Sequência de Aminoácidos , Animais , Transporte Biológico , Caenorhabditis elegans/genética , Feminino , Genes Reporter , Humanos , Leishmania mexicana/genética , Leishmania mexicana/metabolismo , Macrófagos/parasitologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Estrutura Terciária de Proteína , Proteínas de Protozoários/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismo , Alinhamento de Sequência , Virulência
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