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1.
Medicina (B Aires) ; 81(2): 154-158, 2021.
Artículo en Español | MEDLINE | ID: mdl-33906132

RESUMEN

Chagas disease is endemic in Latin America and remains a regional problem despite improvements in environmental health conditions that have helped to control its transmission. To know more about its prevalence in heart disease patients, we carried out a survey in our national (El Salvador) reference hospital. We reviewed the Chagas Lab's records 2013-2015 to find out how many of the patients admitted to the Hospital's Heart Unit were serologically positives for Trypanosoma cruzi infection and which the associated diagnoses were. A total of 1472 patients were tested along the 36-month study period. Out of 557 (37.8%) patients with positive serology for Chagas infection, 97 (17.4%) were eventually admitted to the Heart Unit. Among these 97 Chagas infected patients with heart disease, 40 (41.2%) met the criteria for permanent pacemaker placement, while only 13 of 191 (6.8%) patients with non-chagasic heart disease met these criteria. The frequency of heart atrioventricular block associated with Trypanosoma cruzi infection was higher than frequencies reported in South American studies.


Asunto(s)
Bloqueo Atrioventricular , Enfermedad de Chagas , Trypanosoma cruzi , Bloqueo Atrioventricular/epidemiología , Bloqueo Atrioventricular/etiología , Enfermedad de Chagas/diagnóstico , Enfermedad de Chagas/epidemiología , El Salvador , Humanos , América Latina
2.
Rev Soc Bras Med Trop ; 54: e0740, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33886818

RESUMEN

INTRODUCTION: Chagas disease is a health problem that affects approximately 7 million people worldwide, according to the World Health Organization. Vector transmission is one of the most important routes in South and Central American countries. Between 2013 and 2019, municipalities of Sergipe sent 507 triatomines for analysis, unveiling the largest records found in the south in the villages of Poço da Clara, Alagoinhas and Pilões, and the municipality of Tobias Barreto. The high prevalence of infected vectors in these localities motivated this epidemiological study. METHODS: After educational lectures on the vectors and risks of the disease, a structured questionnaire was administered to identify areas and risk factors for transmission of the parasite. The data guided the collection of vectors and blood samples from domestic reservoirs. RESULTS: The studied region is considered endemic for triatomines infected by Trypanosoma cruzi with three species of vectors; the highest prevalence was Panstrongylus lutzi (54.83%), followed by Triatoma pseudomaculata (43.54%), and Triatoma tibiamaculata (1.61%). In the villages in this study, 100% of the vectors were found intradomically. The coexistence of residents with domestic animals was reported by 62.04% (255) of those surveyed. Forty-one small animals that were actively living with humans at home in the localities were evaluated serologically. No infection was observed in the domestic animals. CONCLUSIONS: There are favorable conditions for the domiciliation of triatomines in the evaluated locations, contributing to the risk of vectorial transmission of Chagas disease.


Asunto(s)
Enfermedad de Chagas , Panstrongylus , Triatoma , Trypanosoma cruzi , Animales , Enfermedad de Chagas/epidemiología , Humanos , Insectos Vectores
3.
Drugs Today (Barc) ; 57(4): 251-263, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33851689

RESUMEN

Chagas disease is a vector-borne neglected tropical disease caused by Trypanosoma cruzi. It is a systemic and chronic parasitic infection which is endemic in 21 countries with 10 million cases worldwide and 12,000 annual deaths. Around 70 million people in the Americas are at risk of contracting this disease, and less than 1% of infected people are treated due to low disease awareness and limited access to treatment. The current treatment for Chagas disease consists of benznidazole and nifurtimox under the World Health Organization (WHO) authorization protocol. The current treatment has limitations in terms of efficacy against the chronic phase of infection and side effects associated with prolonged therapy. This review provides an update on nifurtimox progress over the years and its recent approval by the U.S. Food and Drug Administration (FDA) in 2020 for the treatment of Chagas disease in pediatric patients under 18 years of age.


Asunto(s)
Enfermedad de Chagas , Tripanocidas , Trypanosoma cruzi , Adolescente , Enfermedad de Chagas/diagnóstico , Enfermedad de Chagas/tratamiento farmacológico , Niño , Humanos , Nifurtimox/efectos adversos , Tripanocidas/efectos adversos , Estados Unidos , United States Food and Drug Administration
4.
Eur J Med Chem ; 216: 113290, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33667845

RESUMEN

Kinetoplastid parasites are the causative agents of neglected tropical diseases with an unmet medical need. These parasites are unable to synthesize the purine ring de novo, and therefore rely on purine salvage to meet their purine demand. Evaluating purine nucleoside analogs is therefore an attractive strategy to identify antikinetoplastid agents. Several anti-Trypanosoma cruzi and anti-Trypanosoma brucei 7-deazapurine nucleosides were previously discovered, with the removal of the 3'-hydroxyl group resulting in a significant boost in activity. In this work we therefore decided to assess the effect of the introduction of a 3'-fluoro substituent in 7-deazapurine nucleosides on the anti-kinetoplastid activities. Hence, we synthesized two series of 3'-deoxy-3'-fluororibofuranosyl and 3'-deoxy-3'-fluoroxylofuranosyl nucleosides comprising 7-deazaadenine and -hypoxanthine bases and assayed these for antiparasitic activity. Several analogs with potent activity against T. cruzi and T. brucei were discovered, indicating that a fluorine atom in the 3'-position is a promising modification for the discovery of antiparasitic nucleosides.


Asunto(s)
Nucleósidos de Purina/química , Purinas/química , Tripanocidas/síntesis química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Nucleósidos de Purina/síntesis química , Nucleósidos de Purina/farmacología , Purinas/síntesis química , Purinas/farmacología , Relación Estructura-Actividad , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos
5.
Mem Inst Oswaldo Cruz ; 116: e200634, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33787768

RESUMEN

The availability of Trypanosomatid genomic data in public databases has opened myriad experimental possibilities that have contributed to a more comprehensive understanding of the biology of these parasites and their interactions with hosts. In this review, after brief remarks on the history of the Trypanosoma cruzi and Leishmania genome initiatives, we present an overview of the relevant contributions of genomics, transcriptomics and functional genomics, discussing the primary obstacles, challenges, relevant achievements and future perspectives of these technologies.


Asunto(s)
Genoma de Protozoos/genética , Leishmania/genética , Trypanosoma cruzi/genética , Biología Computacional , Genómica
6.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-33669428

RESUMEN

Chagas disease remains a major social and public health problem in Latin America. Benznidazole (BZN) is the main drug with activity against Trypanosoma cruzi. Due to the high number of adverse drug reactions (ADRs), BZN is underprescribed. The goal of this study was to evaluate the genetic and transcriptional basis of BZN adverse reactions. METHODS: A prospective cohort with 102 Chagas disease patients who underwent BZN treatment was established to identify ADRs and understand their genetic basis. The patients were classified into two groups: those with at least one ADR (n = 73), and those without ADRs (n = 29). Genomic analyses were performed comparing single nucleotide polymorphisms between groups. Transcriptome data were obtained comparing groups before and after treatment, and signaling pathways related to the main ADRs were evaluated. RESULTS: A total of 73 subjects (71.5%) experienced ADRs. Dermatological symptoms were most frequent (45.1%). One region of chromosome 16, at the gene LOC102724084 (rs1518601, rs11861761, and rs34091595), was associated with ADRs (p = 5.652 × 10-8). Transcriptomic data revealed three significantly enriched signaling pathways related to BZN ADRs. CONCLUSIONS: These data suggest that part of adverse BZN reactions might be genetically determined and may facilitate patient risk stratification prior to starting BZN treatment.


Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/genética , Nitroimidazoles/efectos adversos , Polimorfismo de Nucleótido Simple , Transcriptoma , Tripanocidas/efectos adversos , Trypanosoma cruzi/efectos de los fármacos , Brasil/epidemiología , Enfermedad de Chagas/epidemiología , Enfermedad de Chagas/parasitología , Femenino , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Riesgo , Transducción de Señal/genética
7.
Exp Parasitol ; 224: 108100, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33744229

RESUMEN

Chagas disease and leishmaniasis are neglected diseases caused by parasites of the Trypanosomatidae family and together they affect millions of people in the five continents. The treatment of Chagas disease is based on benznidazole, whereas for leishmaniasis few drugs are available, such as amphotericin B and miltefosine. In both cases, the current treatment is not entirely efficient due to toxicity or side effects. Encouraged by the need to discover valid targets and new treatment options, we evaluated 8 furan compounds against Trypanosoma cruzi and Leishmania amazonensis, considering their effects against proliferation, infection, and ultrastructure. Many of them were able to impair T. cruzi and L. amazonensis proliferation, as well as cause ultrastructural alterations, such as Golgi apparatus disorganization, autophagosome formation, and mitochondrial swelling. Taken together, the results obtained so far make these compounds eligible for further steps of chemotherapy study.


Asunto(s)
Furanos/farmacología , Leishmania mexicana/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos , Línea Celular , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Cromatografía en Capa Delgada , Enfermedades Endémicas , Furanos/química , Humanos , Concentración 50 Inhibidora , Leishmania mexicana/crecimiento & desarrollo , Leishmania mexicana/ultraestructura , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/parasitología , Macrófagos , Espectroscopía de Resonancia Magnética , Microscopía Electrónica de Rastreo , Simulación del Acoplamiento Molecular , Enfermedades Desatendidas/tratamiento farmacológico , Enfermedades Desatendidas/parasitología , Trypanosoma cruzi/crecimiento & desarrollo , Trypanosoma cruzi/ultraestructura
8.
Rev Soc Bras Med Trop ; 54: e0269-2020, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33759915

RESUMEN

Reactivation of chronic Trypanosoma cruzi infection in solid organ transplant recipients (SOTRs) has been reported. The patient presented with a 2-week history of two painful erythematous, infiltrated plaques with central ulceration and necrotic crust on the left thigh. She had a history of chronic indeterminate Chagas disease (CD) and had received a kidney transplant before 2 months. Skin biopsies revealed lobular panniculitis with intracellular amastigote forms of T. cruzi. The patient was diagnosed with CD reactivation. Treatment with benznidazole significantly improved her condition. CD reactivation should be suspected in SOTRs living in endemic areas with clinical polymorphism of skin lesions.


Asunto(s)
Enfermedad de Chagas , Trasplante de Riñón , Paniculitis , Trypanosoma cruzi , Enfermedad de Chagas/diagnóstico , Femenino , Humanos , Trasplante de Riñón/efectos adversos , Muslo
9.
Rev Soc Bras Med Trop ; 54: e0873-2020, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33759934

RESUMEN

Chagas disease is caused by the protozoan Trypanosoma cruzi. Seven lineages have been identified based on different molecular markers, namely TcI, TcII, TcIII, TcIV, TcV, TcVI, and TcBat. Dogs play the role of epidemiological sentinels being domestic reservoirs of T. cruzi. The aim of the current study was to report the first case of CD in a domestic dog in Manaus, Amazonas, Brazil, infected with T. cruzi DTU TcIV. We hope our report encourages veterinarians and surveillance professionals to a take a deeper look at T. cruzi infection in domestic animals.


Asunto(s)
Enfermedad de Chagas , Trypanosoma cruzi , Animales , Brasil , Enfermedad de Chagas/diagnóstico , Enfermedad de Chagas/veterinaria , Perros , Genotipo , Trypanosoma cruzi/genética
10.
Artículo en Inglés | MEDLINE | ID: mdl-33681912

RESUMEN

INTRODUCTION: This study estimated the seroprevalence and risk factors of Chagas disease (CD) in a population of the Quixeré municipality, Ceará. METHODS: We conducted serological methods to detect the Trypanosoma cruzi infection. The other variables were evaluated by a standardized questionnaire. RESULTS: The estimated prevalence of CD was 3.7%. Male sex, age >40 years, being farmers, low education level, origin from rural areas, and being born in Quixeré were significantly associated with infection. CONCLUSION: CD persists in this rural population of Northeast Brazil. Poverty, low education, and limited information regarding CD are critical issues that need to be addressed.


Asunto(s)
Enfermedad de Chagas , Trypanosoma cruzi , Adulto , Brasil/epidemiología , Enfermedad de Chagas/epidemiología , Humanos , Masculino , Prevalencia , Factores de Riesgo , Población Rural , Estudios Seroepidemiológicos
11.
Artículo en Inglés | MEDLINE | ID: mdl-33681926

RESUMEN

INTRODUCTION: Triatomines are insect vectors of Trypanosoma cruzi, the etiological agent of Chagas disease. METHODS: Triatomines were collected from households and by dissecting palm trees in the peri-urban areas of Cruzeiro do Sul (Acre); they were identified using a specific key and via genital analyses. Trypanosomatid infection was determined through microscopy and polymerase chain reaction. RESULTS: In total, 116 triatomines of the species Eratyrus mucronatus, Rhodnius pictipes, R. stali, and R. montenegrensis were collected, of which 13.8% were positive for T. cruzi. CONCLUSIONS: Four species of triatomines presented an infection rate above 13% in the Boca do Moa community.


Asunto(s)
Enfermedad de Chagas , Rhodnius , Triatominae , Trypanosoma cruzi , Animales , Brasil
12.
Mem Inst Oswaldo Cruz ; 116: e200528, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33656141

RESUMEN

Panstrongylus geniculatus (Latreille, 1811) is the triatomine with the largest geographic distribution in Latin America. It has been reported in 18 countries from southern Mexico to northern Argentina, including the Caribbean islands. Although most reports indicate that P. geniculatus has wild habitats, this species has intrusive habits regarding human dwellings mainly located in intermediate deforested areas. It is attracted by artificial light from urban and rural buildings, raising the risk of transmission of Trypanosoma cruzi. Despite the wide body of published information on P. geniculatus, many knowledge gaps exist about its biology and epidemiological potential. For this reason, we analysed the literature for P. geniculatus in Scopus, PubMed, Scielo, Google Scholar and the BibTriv3.0 databases to update existing knowledge and provide better information on its geographic distribution, life cycle, genetic diversity, evidence of intrusion and domiciliation, vector-related circulating discrete taxonomic units, possible role in oral T. cruzi transmission, and the effect of climate change on its biology and epidemiology.


Asunto(s)
Enfermedad de Chagas/transmisión , Insectos Vectores/parasitología , Panstrongylus/genética , Panstrongylus/parasitología , Triatoma/parasitología , Trypanosoma cruzi , Animales , Biología , Ecología , Genes de Insecto , Variación Genética/genética , Genotipo , Geografía , Humanos , Insectos Vectores/genética , América Latina , Panstrongylus/fisiología , Filogenia , Trypanosoma cruzi/aislamiento & purificación
13.
Washington, D.C.; OPS; 2021-02-22. (OPS/CDE/VT/20-0042).
No convencional en Español | PAHO-IRIS | ID: phr-53300

RESUMEN

La enfermedad de Chagas o tripanosomiasis americana es una parasitosis sistémica causada por el Trypanosoma cruzi. Su transmisión vectorial se restringe a la Región de las Américas, aunque se puede convertir en un problema de salud de alcance mundial debido a sus modalidades de transmisión transfusional y congénita, y a los movimientos de población desde zonas endémicas. Según las estimaciones, en las Américas hay entre 6 y 8 millones de personas con infección, aproximadamente 30 000 casos nuevos anuales por transmisión vectorial y 8000 casos nuevos anuales por transmisión congénita. Es decir, cerca de 65 millones de personas viven en la Región con el riesgo de contraer la infección; se calcula que esta causa alrededor de 12 000 muertes cada año. La transmisión de T. cruzi de un donante con la enfermedad de Chagas a un receptor de trasplante es poco frecuente y es resultado de la aplicación de un tratamiento quirúrgido. En este documento se proponen diez pautas para manejar y prevenir la transmisión de la enfermedad de Chagas por trasplante de órganos.


Asunto(s)
Enfermedad de Chagas , Tripanosomiasis , Enfermedad de Chagas , Enfermedades Desatendidas , Trypanosoma cruzi , Epidemiología , Américas
14.
Mol Immunol ; 132: 172-183, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33601226

RESUMEN

The trypanosomatid pathogens Leishmania spp., Trypanosoma cruzi, and Trypanosoma brucei, currently grouped as TriTryps, have evolved through the time to overcome the upfront innate immune response and establish the infection in humans adapting many aspects of the parasite-cell host interaction. Extracellular vesicles (EVs) emerge as critical structures carrying different key molecules from parasites and target cells that interact continuously during infection. Current information regarding the structure and composition of these vesicles provide new insights into the primary role of TriTryps-EVs reviewed in this work. Expanding knowledge about these critical vesicular structures will promote advances in basic sciences and in translational applications controlling pathogenesis in the neglected tropical diseases caused by TriTryps.


Asunto(s)
Vesículas Extracelulares/inmunología , Leishmania major/inmunología , Infecciones por Protozoos/inmunología , Trypanosoma brucei brucei/inmunología , Trypanosoma cruzi/inmunología , Animales , Vesículas Extracelulares/parasitología , Interacciones Huésped-Parásitos/inmunología , Humanos , Inmunidad Innata/inmunología , Infecciones por Protozoos/parasitología
15.
Exp Parasitol ; 223: 108079, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33524381

RESUMEN

Chagas disease is caused by Trypanosoma cruzi, and it is an important cause of morbidity and mortality in Latin America. There are no vaccines, and the chemotherapy available to treat this infection has serious side effects. In a search for alternative treatments, we determined the in vitro susceptibility of epimastigote and trypomastigote forms of T. cruzi and the cytotoxic effects on peripheral blood mononuclear cells (PBMCs) of ethanolic extracts obtained from six different plant species. The ethanolic extracts of Ageratina vacciniaefolia, Clethra fimbriata and Siparuna sessiliflora showed antiprotozoal activity against epimastigotes and low cytotoxicity in mammalian cells. However, only the ethanolic extract of C. fimbriata showed activity against T. cruzi trypomastigotes, and it had low cytotoxicity in PBMCs. An analysis on the phytochemical composition of C. fimbriata extract showed that its metabolites were primarily represented by two families of compounds: flavonoids and terpenoids. Lastly, we analyzed whether the A. vacciniaefolia, C. fimbriata, or S. sessiliflora ethanolic extracts induced IFN-γ or TNF-α production. Significantly, ethanolic extracts of C. fimbriata induced TNF-α production and S. sessiliflora induced both cytokines. In addition, C. fimbriata and S. sessiliflora induced the simultaneous secretion of IFN-γ and TNF-α in CD8+ T cells. The antiprotozoal and immunomodulatory activity of C. fimbriata may be related to the presence of flavonoid and triterpene compounds in the extract. Thus, these findings suggest that C. fimbriata may represent a valuable source of new bioactive compounds for the therapeutic treatment of Chagas disease that combines trypanocidal activity with the capacity to boost the immune response.


Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Leucocitos Mononucleares/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Trypanosoma cruzi/efectos de los fármacos , Adulto , Ageratina/química , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Cromatografía Líquida de Alta Presión , Clethraceae/química , Colombia , Femenino , Citometría de Flujo , Humanos , Concentración 50 Inhibidora , Interferón gamma/metabolismo , Laurales/química , Masculino , Medicina Tradicional , Extractos Vegetales/toxicidad , Espectrometría de Masa por Ionización de Electrospray , Factor de Necrosis Tumoral alfa/metabolismo , Adulto Joven
16.
Artículo en Inglés | MEDLINE | ID: mdl-33533811

RESUMEN

Chagas disease (CD) is caused by the protozoan Trypanosoma cruzi and it is mainly acquired through the vector route, however, blood transfusion and congenital transmission are implicated in the spread of the illness worldwide. The congenital route can occur at any stage of pregnancy and its frequency varies. In the Federal District, in Brazil, the frequency of T. cruzi infection in pregnant women and their offspring has not been updated. Thus, the aim of this study was to estimate the prevalence of T. cruzi infection in pregnant women and the rate of congenital transmission in the Federal District. A cross-sectional study was conducted to estimate the seroprevalence of T. cruzi from 2014 to 2016 in the population of pregnant women attended by the public health service throughout the Federal District and a descriptive cohort for the evaluation of congenital transmission. During the study, prenatal data of 98,895 women were consulted and pregnant women registered in 2016, presenting with positive T. cruzi serology, were part of the descriptive cohort. The estimated prevalence of T. cruzi infection in the three years was 0.19% and the congenital transmission rate was 1/40 (2.5%). Our results have shown that, although the main routes of transmission of CD have been interrupted, there is still a risk of congenital transmission in the Federal District. This present study highlights the need for the continuous implementation of a screening program for pregnant women and timely treatment of infected newborns and children.


Asunto(s)
Enfermedad de Chagas/epidemiología , Transmisión Vertical de Enfermedad Infecciosa/estadística & datos numéricos , Complicaciones Parasitarias del Embarazo/epidemiología , Trypanosoma cruzi/aislamiento & purificación , Brasil/epidemiología , Enfermedad de Chagas/diagnóstico , Enfermedad de Chagas/transmisión , Niño , Estudios Transversales , Femenino , Humanos , Recién Nacido , Embarazo , Mujeres Embarazadas , Atención Prenatal , Prevalencia , Estudios Seroepidemiológicos
17.
Eur J Med Chem ; 212: 113101, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33385837

RESUMEN

The kinetoplastid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are the causative agents of neglected tropical diseases with a serious burden in several parts of the world. These parasites are incapable of synthesizing purines de novo, and therefore rely on ingenious purine salvage pathways to acquire and process purines from their host. Purine nucleoside analogs that may interfere with these pathways therefore constitute a privileged source of new antikinetoplastid agents. In this study, we synthetized a collection of C-nucleosides employing five different heterocyclic nucleobase surrogates. C-nucleosides are chemically and enzymatically stable and allow for extensive structural modification. Inspired by earlier 7-deazaadenosine nucleosides and known antileishmanial C-nucleosides, we introduced different modifications tailored towards antikinetoplastid activity. Both adenosine and inosine analogs were synthesized with the aim of discovering new antikinetoplastid hits and expanding knowledge of structure-activity relationships. Several promising hits with potent activity against Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum were discovered, and the nature of the nucleobase surrogate was found to have a profound influence on the selectivity profile of the compounds.


Asunto(s)
Antiprotozoarios/farmacología , Leishmania infantum/efectos de los fármacos , Nucleósidos/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Nucleósidos/síntesis química , Nucleósidos/química , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad
18.
Molecules ; 26(2)2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33467422

RESUMEN

Chagas disease (CD) still represents a serious public health problem in Latin America, even after more than 100 years of its discovery. Clinical treatments (nifurtimox and benznidazole) are considered inadequate, especially because of undesirable side effects and low efficacy in the chronic stages of the disease, highlighting the urgency for discovering new effective and safe drugs. A small library of compounds (1a-i and 2a-j) was designed based on the structural optimization of a Hit compound derived from 1,4-naphthoquinones (C2) previously identified. The biological activity, structure-activity relationship (SAR), and the in silico physicochemical profiles of the naphthoquinone derivatives were analyzed. Most modifications resulted in increased trypanocidal activity but some substitutions also increased toxicity. The data reinforce the importance of the chlorine atom in the thiophenol benzene ring for trypanocidal activity, highlighting 1g, which exhibit a drug-likeness profile, as a promising compound against Trypanosoma cruzi. SAR analysis also revealed 1g as cliff generator in the structure-activity similarity map (SAS maps). However, compounds C2 and 1g were unable to reduce parasite load, and did not prevent mouse mortality in T. cruzi acute infection. Phenotypic screening and computational analysis have provided relevant information to advance the optimization and design of new 1,4-naphthoquinone derivatives with a better pharmacological profile.


Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Naftoquinonas/química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Enfermedad de Chagas/parasitología , Química Computacional , Masculino , Ratones , Estructura Molecular , Naftoquinonas/farmacología , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Tripanocidas/química
19.
Int J Mol Sci ; 22(2)2021 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-33445756

RESUMEN

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC50 = 0.27 µmol L-1) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages.


Asunto(s)
Metabolismo Energético/efectos de los fármacos , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/metabolismo , Animales , Biomarcadores , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/química , Humanos , Redes y Vías Metabólicas/efectos de los fármacos , Ratones , Conformación Molecular , Relación Estructura-Actividad , Tripanocidas/química
20.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33466510

RESUMEN

Ca2+ signaling has been involved in controling critical cellular functions such as activation of proteases, cell death, and cell cycle control. The endoplasmatic reticulum plays a significant role in Ca2+ storage inside the cell, but mitochondria have long been recognized as a fundamental Ca2+ pool. Protozoan parasites such as Plasmodium falciparum, Toxoplasma gondii, and Trypanosoma cruzi display a Ca2+ signaling toolkit with similarities to higher eukaryotes, including the participation of mitochondria in Ca2+-dependent signaling events. This review summarizes the most recent knowledge in mitochondrial Ca2+ signaling in protozoan parasites, focusing on the mechanism involved in mitochondrial Ca2+ uptake by pathogenic protists.


Asunto(s)
Señalización del Calcio/fisiología , Calcio/metabolismo , Mitocondrias/metabolismo , Parásitos/metabolismo , Animales , Eucariontes/metabolismo , Humanos , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/metabolismo , Toxoplasma/metabolismo , Trypanosoma cruzi/metabolismo
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