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1.
Nat Commun ; 12(1): 1052, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594070

RESUMO

The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.


Assuntos
Glicólise/efeitos dos fármacos , Fosfofrutoquinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Trypanosoma/enzimologia , Tripanossomíase Africana/metabolismo , Tripanossomíase Africana/parasitologia , Doença Aguda , Regulação Alostérica/efeitos dos fármacos , Animais , Células Hep G2 , Humanos , Concentração Inibidora 50 , Estimativa de Kaplan-Meier , Camundongos , Parasitos/efeitos dos fármacos , Fosfofrutoquinases/química , Fosfofrutoquinases/metabolismo , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Multimerização Proteica , Relação Estrutura-Atividade , Trypanosoma/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico
2.
PLoS Negl Trop Dis ; 14(9): e0008588, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925917

RESUMO

BACKGROUND: Significant efforts to control human African trypanosomiasis (HAT) over the two past decades have resulted in drastic decrease of its prevalence in Côte d'Ivoire. In this context, passive surveillance, integrated in the national health system and based on clinical suspicion, was reinforced. We describe here the health-seeking pathway of a girl who was the first HAT patient diagnosed through this strategy in August 2017. METHODS: After definitive diagnosis of this patient, epidemiological investigations were carried out into the clinical evolution and the health and therapeutic itinerary of the patient before diagnosis. RESULTS: At the time of diagnosis, the patient was positive in both serological and molecular tests and trypanosomes were detected in blood and cerebrospinal fluid. She suffered from important neurological disorders. The first disease symptoms had appeared three years earlier, and the patient had visited several public and private peripheral health care centres and hospitals in different cities. The failure to diagnose HAT for such a long time caused significant health deterioration and was an important financial burden for the family. CONCLUSION: This description illustrates the complexity of detecting the last HAT cases due to complex diagnosis and the progressive disinterest and unawareness by both health professionals and the population. It confirms the need of implementing passive surveillance in combination with continued sensitization and health staff training.


Assuntos
Diagnóstico Tardio/economia , Doenças Negligenciadas/diagnóstico , Doenças Negligenciadas/tratamento farmacológico , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/tratamento farmacológico , Sangue/parasitologia , Líquido Cefalorraquidiano/parasitologia , Criança , Indicadores de Doenças Crônicas , Costa do Marfim/epidemiologia , Feminino , Humanos , Doenças Negligenciadas/parasitologia , Administração dos Cuidados ao Paciente/economia , Trypanosoma brucei gambiense/isolamento & purificação , Tripanossomíase Africana/parasitologia
3.
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
4.
Exp Parasitol ; 216: 107943, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32598890

RESUMO

The search for novel therapeutic candidates against animal trypanosomiasis is an ongoing scientific endevour because of the negative impacts of the disease to the African livestock industry. In this study, the in vivo therapeutic potentials of phytol toward Trypanosoma congolense infection and the inhibitory effects on trypanosomal sialidase were investigated. Rats were infected with T. congolense and administered daily oral treatment of 50 and 100 mg/kg BW of phytol. Within the first 10 days of the treatment, no antitrypanosomal activity was recorded but a moderate trypanostatic activity was observed from day 17-day 21 pi. However, at 100 mg/kg BW, phytol demonstrated a significant (p < 0.05) ameliorative potentials toward T. congolense-induced host-associated pathological damages such as anaemia, hepatic and renal damages; and the data was comparable to diminazine aceturate. Moreover, the T. congolense caused a significant (p < 0.05) increase in free serum sialic acid level which was significantly (p < 0.05) prevented in the presence of phytol (100 mg/kg BW). In an in vitro analysis, phytol inhibited partially purified T. congolense sialidase using an uncompetitive inhibition pattern with inhibition binding constant of 261.24 µmol/mL. Subsequently, molecular docking revealed that the compound binds to homology modelled trypanosomal sialidase with a binding free energy of -6.7 kcal/mol which was mediated via a single hydrogen bond while Trp324 and Pro274 were the critical binding residues. We concluded that phytol has moderate trypanostatic activity but with a great potential in mitigating the host-associated cellular damages while the anaemia amelioration was mediated, in part, through the inhibition of sialidase.


Assuntos
Antiprotozoários/uso terapêutico , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Fitol/uso terapêutico , Trypanosoma congolense/efeitos dos fármacos , Tripanossomíase Africana/veterinária , Animais , Antiprotozoários/farmacologia , Inibidores Enzimáticos/uso terapêutico , Gado , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/veterinária , Neuraminidase/química , Neuraminidase/isolamento & purificação , Fitol/farmacologia , Distribuição Aleatória , Ratos , Ratos Wistar , Trypanosoma congolense/enzimologia , Tripanossomíase Africana/tratamento farmacológico
5.
Lancet infect. dis ; 20(2): [E38-E46], Feb. 01, 2020.
Artigo em Inglês | BIGG - guias GRADE | ID: biblio-1117170

RESUMO

Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a parasitic infection that usually progresses to coma and death unless treated. WHO has updated its guidelines for the treatment of this infection on the basis of independent literature reviews and using the Grading of Recommendations Assessment, Development and Evaluation methodology. The first-line treatment options, pentamidine and nifurtimox­eflornithine combination therapy, have been expanded to include fexinidazole, an oral monotherapy given a positive opinion from the European Medicines Agency. Fexinidazole is recommended for individuals who are aged 6 years and older with a bodyweight of 20 kg or more, who have first-stage or second-stage gambiense human African trypanosomiasis and a cerebrospinal fluid leucocyte count less than 100 per µL. Nifurtimox­eflornithine combination therapy remains recommended for patients with 100 leucocytes per µL or more. Without clinical suspicion of severe second-stage disease, lumbar puncture can be avoided and fexinidazole can be given. Fexinidazole should only be administered under supervision of trained health staff. Because these recommendations are expected to change clinical practice considerably, health professionals should consult the detailed WHO guidelines. These guidelines will be updated as evidence accrues.


Assuntos
Humanos , Pentamidina/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma brucei gambiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Nifurtimox/uso terapêutico , Nitroimidazóis/uso terapêutico , Tripanossomíase Africana/parasitologia , Líquido Cefalorraquidiano/parasitologia , Quimioterapia Combinada
7.
PLoS Negl Trop Dis ; 14(1): e0008028, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31986140

RESUMO

BACKGROUND: Nifurtimox eflornithine combination therapy (NECT) to treat human African trypanosomiasis (HAT), commonly called sleeping sickness, was added to the World Health Organisation's (WHO) Essential Medicines List in 2009 and to the Paediatric List in 2012. NECT was further tested and documented in a phase IIIb clinical trial in the Democratic Republic of Congo (DRC) assessing the safety, effectiveness, and feasibility of implementation under field conditions (NECT-FIELD study). This trial brought a unique possibility to examine concomitant drug management. METHODOLOGY/PRINCIPAL FINDINGS: This is a secondary analysis of the NECT-FIELD study where 629 second stage gambiense HAT patients were treated with NECT, including children and pregnant and breastfeeding women in six general reference hospitals located in two provinces. Concomitant drugs were prescribed by the local investigators as needed. Patients underwent daily evaluations, including vital signs, physical examination, and adverse event monitoring. Concomitant medication was documented from admission to discharge. Patients' clinical profiles on admission and safety profile during specific HAT treatment were similar to previously published reports. Prescribed concomitant medications administered during the hospitalization period, before, during, and immediately after NECT treatment, were mainly analgesics/antipyretics, anthelmintics, antimalarials, antiemetics, and sedatives. Use of antibiotics was reasonable and antibiotics were often prescribed to treat cellulitis and respiratory tract infections. Prevention and treatment of neurological conditions such as convulsions, loss of consciousness, and coma was used in approximately 5% of patients. CONCLUSIONS/SIGNIFICANCE: The prescription of concomitant treatments was coherent with the clinical and safety profile of the patients. However, some prescription habits would need to be adapted in the future to the evolving available pharmacopoeia. A list of minimal essential medication that should be available at no cost to patients in treatment wards is proposed to help the different actors to plan, manage, and adequately fund drug supplies for advanced HAT infected patients. TRIAL REGISTRATION NUMBER: The initial study was registered at ClinicalTrials.gov, number NCT00906880.


Assuntos
Eflornitina/uso terapêutico , Nifurtimox/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma brucei gambiense , Tripanossomíase Africana/tratamento farmacológico , República Democrática do Congo/epidemiologia , Quimioterapia Combinada , Eflornitina/administração & dosagem , Humanos , Nifurtimox/administração & dosagem , Resultado do Tratamento , Tripanossomíase Africana/epidemiologia
8.
Eur J Med Chem ; 189: 112043, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31978782

RESUMO

Polyamides-based compounds related to the Streptomycetal distamycin and netropsin are potent cytostatic molecules that bind to AT-rich regions of the minor groove of the DNA, hence interfering with DNA replication and transcription. Recently, derivatives belonging to this scaffold have been reported to halt the proliferation of deadly African trypanosomes by different and unrelated mechanisms. Here we describe the synthesis and preliminary characterization of the anti-trypanosomal mode of action of new potent and selective distamycin analogues. Two tri-heterocyclic derivatives containing a central N-methyl pyrrole ring (16 and 17) displayed high activity (EC50 < 20 nM) and selectivity (selectivity index >5000 with respect to mammalian macrophages) against the infective form of T. brucei. Both compounds caused cell cycle arrest by blocking the replication of the mitochondrial DNA but without affecting its integrity. This mode of action clearly differs from that reported for classical minor groove binder (MGB) drugs, which induce the degradation of the mitochondrial DNA. In line with this, in vitro assays suggest that 16 and 17 have a comparatively lower affinity for different template DNAs than the MGB drug diminazene. Therapeutic efficacy studies and stability assays suggest that the pharmacological properties of the hits should be optimized. The compounds can be rated as excellent scaffolds for the design of highly potent and selective anti-T. brucei agents.


Assuntos
Ciclo Celular/efeitos dos fármacos , Distamicinas/química , Macrófagos/efeitos dos fármacos , Tiazóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Animais , Feminino , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Tiazóis/química , Tripanossomicidas/química , Trypanosoma/parasitologia , Tripanossomíase Africana/parasitologia
9.
J Med Chem ; 63(2): 756-783, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31846577

RESUMO

From a high-throughput screen of 42 444 known human kinases inhibitors, a pyrazolo[1,5-b]pyridazine scaffold was identified to begin optimization for the treatment of human African trypanosomiasis. Previously reported data for analogous compounds against human kinases GSK-3ß, CDK-2, and CDK-4 were leveraged to try to improve the selectivity of the series, resulting in 23a which showed selectivity for T. b. brucei over these three human enzymes. In parallel, properties known to influence the absorption, distribution, metabolism, and excretion (ADME) profile of the series were optimized resulting in 20g being progressed into an efficacy study in mice. Though 20g showed toxicity in mice, it also demonstrated CNS penetration in a PK study and significant reduction of parasitemia in four out of the six mice.


Assuntos
Piridazinas/síntese química , Piridazinas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Tripanossomíase Africana/tratamento farmacológico , Animais , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Reposicionamento de Medicamentos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Leishmania donovani/efeitos dos fármacos , Camundongos , Modelos Moleculares , Piridazinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato , Distribuição Tecidual , Tripanossomicidas/farmacocinética , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/parasitologia
10.
Lancet Infect Dis ; 20(2): e38-e46, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31879061

RESUMO

Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a parasitic infection that usually progresses to coma and death unless treated. WHO has updated its guidelines for the treatment of this infection on the basis of independent literature reviews and using the Grading of Recommendations Assessment, Development and Evaluation methodology. The first-line treatment options, pentamidine and nifurtimox-eflornithine combination therapy, have been expanded to include fexinidazole, an oral monotherapy given a positive opinion from the European Medicines Agency. Fexinidazole is recommended for individuals who are aged 6 years and older with a bodyweight of 20 kg or more, who have first-stage or second-stage gambiense human African trypanosomiasis and a cerebrospinal fluid leucocyte count less than 100 per µL. Nifurtimox-eflornithine combination therapy remains recommended for patients with 100 leucocytes per µL or more. Without clinical suspicion of severe second-stage disease, lumbar puncture can be avoided and fexinidazole can be given. Fexinidazole should only be administered under supervision of trained health staff. Because these recommendations are expected to change clinical practice considerably, health professionals should consult the detailed WHO guidelines. These guidelines will be updated as evidence accrues.


Assuntos
Antiprotozoários/uso terapêutico , Nitroimidazóis/uso terapêutico , Guias de Prática Clínica como Assunto , Trypanosoma brucei gambiense/isolamento & purificação , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Eflornitina/uso terapêutico , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Nifurtimox/uso terapêutico , Organização Mundial da Saúde , Adulto Jovem
11.
J Med Chem ; 63(5): 2527-2546, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31670951

RESUMO

Human African trypanosomiasis (HAT) is a neglected tropical disease caused by infection with either of two subspecies of the parasite Trypanosoma brucei. Due to a lack of economic incentive to develop new drugs, current treatments have severe limitations in terms of safety, efficacy, and ease of administration. In an effort to develop new HAT therapeutics, we report the structure-activity relationships around T. brucei for a series of benzoxazepinoindazoles previously identified through a high-throughput screen of human kinase inhibitors, and the subsequent in vivo experiments for HAT. We identified compound 18, which showed an improved kinase selectivity profile and acceptable pharmacokinetic parameters, as a promising lead. Although treatment with 18 cured 60% of mice in a systemic model of HAT, the compound was unable to clear parasitemia in a CNS model of the disease. We also report the results of cross-screening these compounds against T. cruzi, L. donovani, and S. mansoni.


Assuntos
Indazóis/química , Indazóis/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Animais , Feminino , Humanos , Indazóis/farmacocinética , Camundongos , Oxazepinas/química , Oxazepinas/farmacocinética , Oxazepinas/farmacologia , Testes de Sensibilidade Parasitária , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/farmacocinética
12.
Molecules ; 24(23)2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31817023

RESUMO

Essential oil of Origanum species is well known for antimicrobial activity, but only a few have been evaluated in narrow spectrum antiprotozoal assays. Herein, we assessed the antiprotozoal potential of Turkish Origanum onites L. oil and its major constituents against a panel of parasitic protozoa. The essential oil was obtained by hydrodistillation from the dried herbal parts of O. onites and analyzed by Gas Chromatography-Flame Ionization Detector (GC-FID) and Gas Chromatography coupled with Mass Spectrometry (GC-MS). The in vitro activity of the oil and its major components were evaluated against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum. The main component of the oil was identified as carvacrol (70.6%), followed by linalool (9.7%), p-cymene (7%), γ-terpinene (2.1%), and thymol (1.8%). The oil showed significant in vitro activity against T. b. rhodesiense (IC50 180 ng/mL), and moderate antileishmanial and antiplasmodial effects, without toxicity to mammalian cells. Carvacrol, thymol, and 10 additional abundant oil constituents were tested against the same panel; carvacrol and thymol retained the oil's in vitro antiparasitic potency. In the T. b. brucei mouse model, thymol, but not carvacrol, extended the mean survival of animals. This study indicates the potential of the essential oil of O. onites and its constituents in the treatment of protozoal infections.


Assuntos
Antiprotozoários/administração & dosagem , Antiprotozoários/química , Óleos Voláteis/administração & dosagem , Óleos Voláteis/química , Origanum/química , Tripanossomíase Africana/tratamento farmacológico , Animais , Antiprotozoários/farmacologia , Cimenos/administração & dosagem , Cimenos/farmacologia , Modelos Animais de Doenças , Cromatografia Gasosa-Espectrometria de Massas , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Óleos Voláteis/farmacologia , Óleos Vegetais/química , Óleos Vegetais/farmacologia , Timol/administração & dosagem , Timol/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos
13.
Nat Commun ; 10(1): 5564, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804484

RESUMO

African trypanosomiasis is a disease caused by Trypanosoma brucei parasites with limited treatment options. Trypanosoma is unable to synthesize purines de novo and relies solely on their uptake and interconversion from the host, constituting purine nucleoside analogues a potential source of antitrypanosomal agents. Here we combine structural elements from known trypanocidal nucleoside analogues to develop a series of 3'-deoxy-7-deazaadenosine nucleosides, and investigate their effects against African trypanosomes. 3'-Deoxytubercidin is a highly potent trypanocide in vitro and displays curative activity in animal models of acute and CNS-stage disease, even at low doses and oral administration. Whole-genome RNAi screening reveals that the P2 nucleoside transporter and adenosine kinase are involved in the uptake and activation, respectively, of this analogue. This is confirmed by P1 and P2 transporter assays and nucleotide pool analysis. 3'-Deoxytubercidin is a promising lead to treat late-stage sleeping sickness.


Assuntos
Desoxiadenosinas/farmacologia , Proteínas de Transporte de Nucleosídeos/metabolismo , Proteínas de Protozoários/metabolismo , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Tubercidina/farmacologia , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular , Sobrevivência Celular , Desoxiadenosinas/química , Quimioterapia Combinada , Feminino , Humanos , Camundongos , Estrutura Molecular , Proteínas de Transporte de Nucleosídeos/genética , Proteínas de Protozoários/genética , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/genética , Trypanosoma brucei brucei/fisiologia , Tripanossomíase Africana/parasitologia , Tubercidina/química
14.
Drugs Today (Barc) ; 55(11): 705-712, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31840685

RESUMO

On November 15, 2018, Fexinidazole Winthrop received a positive opinion from the European Medicines Agency (EMA) (under Article 58) for treatment of first-stage (hemolymphatic) and second-stage (meningoencephalitic) human African trypanosomiasis caused by Trypanosoma gambiense (gHAT) in adults and children 6 years and older and weighing 20 or more kg. This is the first oral regimen for gHAT that is effective in treating both disease stages. Although fexinidazole has potential to simplify current therapies, it does not entirely eliminate the need for disease staging by lumbar puncture because patients with severe stage 2 disease (CSF WBC [cerebrospinal fluid white blood cells] greater than 100 cells/µL) should only be treated with fexinidazole if no other suitable treatment is available. Nausea and vomiting are a common side effect and the drug must be administered during or after the patient's main meal under direct observation by trained health personnel. Due to late relapses, the EMA recommends follow-up to 24 months after treatment.


Assuntos
Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Humanos
15.
J Med Chem ; 62(23): 10617-10629, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714776

RESUMO

This paper describes an optimization strategy of the highly active vinyl ketone 3 which was recognized as a strong inhibitor of rhodesain of Trypanosoma brucei rhodesiense, endowed with a ksecond value of 67 × 106 M-1 min-1 coupled with a high binding affinity (Ki = 38 pM). We now report a new structure-activity relationship study based on structural variations on the P3, P2, and P1' sites which led us to identify two potent lead compounds, i.e., vinyl ketones 4h and 4k. Vinyl ketone 4h showed an impressive potency toward rhodesain (ksecond = 8811 × 105) coupled to a good antiparasitic activity (EC50 = 3.6 µM), while vinyl ketone 4k proved to possess the highest binding affinity toward the trypanosomal protease (Ki = 0.6 pM) and a submicromolar antiparasitic activity (EC50 = 0.67 µM), thus representing new lead compounds in the drug discovery process for the treatment of Human African Trypanosomiasis.


Assuntos
Cisteína Endopeptidases/metabolismo , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Humanos , Estrutura Molecular , Conformação Proteica , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia , Trypanosoma brucei rhodesiense/metabolismo
17.
Parasitology ; 146(14): 1743-1754, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31603063

RESUMO

Kinetoplastid parasites are responsible for serious diseases in humans and livestock such as Chagas disease and sleeping sickness (caused by Trypanosoma cruzi and Trypanosoma brucei, respectively), and the different forms of cutaneous, mucocutaneous and visceral leishmaniasis (produced by Leishmania spp). The limited number of antiparasitic drugs available together with the emergence of resistance underscores the need for new therapeutic agents with novel mechanisms of action. The use of agents binding to surface glycans has been recently suggested as a new approach to antitrypanosomal design and a series of peptidic and non-peptidic carbohydrate-binding agents have been identified as antiparasitics showing efficacy in animal models of sleeping sickness. Here we provide an overview of the nature of surface glycans in three kinetoplastid parasites, T. cruzi, T. brucei and Leishmania. Their role in virulence and host cell invasion is highlighted with the aim of identifying specific glycan-lectin interactions and carbohydrate functions that may be the target of novel carbohydrate-binding agents with therapeutic applications.


Assuntos
Antiparasitários/farmacologia , Carboidratos/imunologia , Interações Hospedeiro-Parasita/efeitos dos fármacos , Gado/parasitologia , Polissacarídeos/imunologia , Animais , Doença de Chagas/tratamento farmacológico , Desenho de Fármacos , Humanos , Leishmania/efeitos dos fármacos , Leishmania/patogenicidade , Camundongos , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/patogenicidade , Tripanossomíase Africana/tratamento farmacológico
18.
Protein Expr Purif ; 164: 105465, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31377239

RESUMO

The metacaspases (MCAs) are attractive drug targets for the treatment of African trypanosomiasis as they are not found in the metazoan kingdom and their action has been implicated in cell cycle and cell death pathways in kinetoplastid parasites. Here we report the biochemical characterisation of MCA5 from T. congolense. Upon recombinant expression in E. coli, autoprocessing is evident, and MCA5 further autoprocesses when purified using nickel affinity chromatography, which we term nickel-induced over autoprocessing. When both the catalytic His and Cys residues were mutated (TcoMCA5H147A/C202G), no nickel-induced over autoprocessing was observed and was enzymatically active, suggesting the existence of a secondary catalytic Cys residue, Cys81. Immunoaffinity purification of native TcoMCA5 from the total parasite proteins was achieved using chicken anti-TcoMCA5 IgY antibodies. The full length native TcoMCA5 and the autoprocessed products of recombinant TcoMCA5H147A/C202G were shown to possess gelatinolytic activity, the first report for that of a MCA. Both the native and recombinant enzyme were calcium independent, had a preference for Arg over Lys at the P1 site and were active over a pH range between 6.5 and 9. Partial inhibition (23%) of enzymatic activity was only achieved with leupeptin and antipain. These findings are the first step in the biochemical characterisation of the single copy MCAs from animal infective trypanosomes towards the design of novel trypanocides.


Assuntos
Trypanosoma congolense/enzimologia , Tripanossomíase Africana/parasitologia , Animais , Clonagem Molecular , Gelatinases/genética , Gelatinases/isolamento & purificação , Gelatinases/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Especificidade por Substrato , Trypanosoma congolense/genética , Trypanosoma congolense/metabolismo , Tripanossomíase Africana/tratamento farmacológico
19.
Molecules ; 24(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374887

RESUMO

Dithiocarbamates represent a class of compounds that were evaluated in different biomedical applications because of their chemical versatility. For this reason, several pharmacological activities have already been attributed to these compounds, such as antiparasitic, antiviral, antifungal activities, among others. Therefore, compounds that are based on dithiocarbamates have been evaluated in different in vivo and in vitro models as potential new antimicrobials. Thus, the purpose of this review is to present the possibilities of using dithiocarbamate compounds as potential new antitrypanosomatids-drugs, which could be used for the pharmacological control of Chagas disease, leishmaniasis, and African trypanosomiasis.


Assuntos
Antiparasitários/uso terapêutico , Leishmaniose/tratamento farmacológico , Tiocarbamatos/uso terapêutico , Trypanosoma/efeitos dos fármacos , Animais , Antiparasitários/química , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Humanos , Leishmaniose/parasitologia , Tiocarbamatos/química , Trypanosoma/patogenicidade , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia
20.
Future Med Chem ; 11(13): 1537-1551, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31469332

RESUMO

Aim: Limitations in available therapies for trypanosomiases indicate the need for improved medicines. Cysteine proteases cruzain and rhodesain are validated targets for treatment of Chagas disease and human African trypanosomiasis. Previous studies reported a benzimidazole series as potent cruzain inhibitors. Results & methodology: Considering the high similarity between these proteases, we evaluated 40 benzimidazoles against rhodesain. We describe their structure-activity relationships (SAR), revealing trends similar to those observed for cruzain and features that lead to enzyme selectivity. This series comprises noncovalent competitive inhibitors (best Ki = 0.21 µM against rhodesain) and micromolar activity against Trypanosoma brucei brucei. A cheminformatics analysis confirms scaffold novelty, and the inhibitors described have favorable predicted physicochemical properties. Conclusion: Our results support this series as a starting point for new human African trypanosomiasis medicines.


Assuntos
Benzimidazóis/farmacologia , Cisteína Proteases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Benzimidazóis/síntese química , Benzimidazóis/química , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Relação Dose-Resposta a Droga , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma brucei brucei/enzimologia , Tripanossomíase Africana/tratamento farmacológico
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