scholarly journals Análise e caracterização de um promissor alvo terapêutico identificado em Leishmania spp

Author(s):  
Fernando de Sá Ribeiro ◽  
Jéssica Barbosa de Jesus ◽  
Alessandra Mendonça Teles de Souza

A Leishmaniose é uma doença negligenciada causada por protozoários do gênero Leishmania spp., o qual atinge cerca de 1,6 milhão indivíduos a cada ano sendo que 500 mil se apresentam na forma visceral. No Brasil ocorrem cerca de 30.000 novos casos a cada ano. Além disso, o país é responsável por 90% dos casos notificados de Leishmaniose Visceral, sendo essa forma mais grave da doença. Aliado a esses fatos, o tratamento vigente se mostra ineficaz, contribuindo para o estabelecimento de cepas resistentes. Atualmente, o tratamento apresenta diversos efeitos colaterais e danos permanentes à saúde dos pacientes, tal fato têm contribuído para a procura de novos fármacos contra a leishmaniose. A enzima oligopeptidase B (OPB) tem sido estudada como possível alvo terapêutico no desenvolvimento de agentes antiparasitários. Desta forma, o objetivo desse trabalho é construir o modelo tridimensional da enzima Oligopeptidase B de diferentes espécies de Leishmania spp. e compara-las entre si. Para tal, foi utilizado o método de modelagem comparativa. Nesse método foi feita a construção dos modelos das espécies L. brasiliensis, L. donovani, L. infantum, L. mexicana e L. panamensis, utilizando o programa MODELLER. Uma vez com os modelos prontos foram realizados o processo de validação dos mesmos e subsequentemente caracterizados, o qual foi possível constatar um grau de semelhança promissor entre os modelos. Por fim, tais modelos foram submetidos ao método de análise por modos normais, os quais obtiveram um padrão de movimento semelhante, com isso foi possível constatar um movimento em uma região específica de uma alfa-hélice, levando consequentemente a tríade da enzima se mostrar exposta, podendo ser indicativo de um mecanismo de ação. Por fim, espera-se utilizar os modelos construídos para auxiliar no desenvolvimento de uma nova terapia promissora para o tratamento da leishmaniose.

Author(s):  
Fernando de Sá Ribeiro ◽  
Jéssica Barbosa de Jesus ◽  
Alessandra Mendonça Teles de Souza

Leishmaniasis is a neglected disease caused by protozoa of the genus Leishmania spp., which affects about 1.6 million individuals each year and 500,000 present themselves in the visceral form. In Brazil there are about 30,000 new cases each year. In addition, the country is responsible for 90% of reported cases of Visceral Leishmaniasis, and this is more severe form of the disease. Allied to these facts, the current treatment is ineffective, contributing to the establishment of resistant strains. Currently, the treatment has several side effects and permanent damage to the health of patients, this fact has contributed to the search for new drugs against leishmaniasis. The enzyme oligopeptidase B (OPB) has been studied as a possible therapeutic target in the development of antiparasitic agents. Thus, the objective of this work is to construct the three-dimensional model of the enzyme Oligopeptidase B of different species of Leishmania spp. and compare them to each other. For this purpose, the comparative modeling method was used. In this method, the models of the species L. brasiliensis, L. donovani, L. infantum, L. mexicana and L. panamensis were constructed using the MODELLER program. Once the models were ready, the validation process was carried out and subsequently characterized, which was possible to verify a promising degree of similarity between the models. Finally, these models were submitted to the method of analysis by normal modes, which obtained a similar movement pattern, thus it was possible to verify a movement in a specific region of an alpha-helix, consequently leading to the triad of the enzyme being exposed, which may be indicative of a mechanism of action. Finally, it is expected to use the models built to assist in the development of a promising new therapy for the treatment of leishmaniasis.


2020 ◽  
Vol 27 ◽  
Author(s):  
Antonio Moreno-Herrera ◽  
Sandra Cortez-Maya ◽  
Virgilio Bocanegra-Garcia ◽  
Bimal Krishna Banik ◽  
Gildardo Rivera

: Infections caused by Trypanosoma brucei, Trypanosoma cruzi, Leishmania spp., Entamoeba histolytica, Giardia lamblia, Plasmodium spp., and Trichomonas vaginalis, are part of a large list of human parasitic diseases. Together, they cause more than 500 million infections per year. These protozoa parasites affect both low- and high-income countries and their pharmacological treatment is limited. Therefore, new and more effective drugs in preclinical development could improve overall therapy for parasitic infections even when their mechanisms of action are unknown. In this review, a number of heterocyclic compounds (diamidine, guanidine, quinoline, benzimidazole, thiazole, diazanaphthalene, and their derivatives) reported as antiprotozoal agents are discussed as options for developing new pharmacological treatments for parasitic diseases.


2020 ◽  
Vol 26 ◽  
Author(s):  
Luíza Dantas-Pereira ◽  
Edézio F. Cunha-Junior ◽  
Valter V. Andrade-Neto ◽  
John F. Bower ◽  
Guilherme A. M. Jardim ◽  
...  

: Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo are essential for the development of a novel, specific and safe derivative, minimizing adverse effects.


2017 ◽  
Vol 17 (11) ◽  
pp. 1303-1317 ◽  
Author(s):  
Marta Branquinha ◽  
Leandro Sangenito ◽  
Catia Sodre ◽  
Lucimar Kneipp ◽  
Claudia d'Avila-Levy ◽  
...  

2015 ◽  
Vol 59 (5) ◽  
pp. 2867-2874 ◽  
Author(s):  
Atteneri López-Arencibia ◽  
Daniel García-Velázquez ◽  
Carmen M. Martín-Navarro ◽  
Ines Sifaoui ◽  
María Reyes-Batlle ◽  
...  

ABSTRACTThein vitroactivity of a novel group of compounds, hexaazatrinaphthylene derivatives, against two species ofLeishmaniais described in this study. These compounds showed a significant dose-dependent inhibition effect on the proliferation of the parasites, with 50% inhibitory concentrations (IC50s) ranging from 1.23 to 25.05 μM against the promastigote stage and 0.5 to 0.7 μM against intracellular amastigotes. Also, a cytotoxicity assay was carried out to in order to evaluate the possible toxic effects of these compounds. Moreover, different assays were performed to determine the type of cell death induced after incubation with these compounds. The obtained results highlight the potential use of hexaazatrinaphthylene derivatives againstLeishmaniaspecies, and further studies should be undertaken to establish them as novel leishmanicidal therapeutic agents.


2021 ◽  
Author(s):  
Fabián Espitia-Almeida ◽  
Carlos Díaz-Uribe ◽  
William Vallejo ◽  
Orlando Peña ◽  
Doris Gómez-Camargo ◽  
...  

2021 ◽  
Vol 22 (8) ◽  
pp. 4209
Author(s):  
Karolina Kot ◽  
Natalia Łanocha-Arendarczyk ◽  
Michał Ptak ◽  
Aleksandra Łanocha ◽  
Elżbieta Kalisińska ◽  
...  

Leishmaniasis, malaria, toxoplasmosis, and acanthamoebiasis are protozoan parasitic infections. They remain important contributors to the development of kidney disease, which is associated with increased patients’ morbidity and mortality. Kidney injury mechanisms are not fully understood in protozoan parasitic diseases, bringing major difficulties to specific therapeutic interventions. The aim of this review is to present the biochemical and molecular mechanisms in kidneys infected with Leishmania spp., Plasmodium spp., Toxoplasma gondii, and Acanthamoeba spp. We present available mechanisms of an immune response, oxidative stress, apoptosis process, hypoxia, biomarkers of renal injury in the serum or urine, and the histopathological changes of kidneys infected with the selected parasites. Pathomechanisms of Leishmania spp. and Plasmodium spp. infections have been deeply investigated, while Toxoplasma gondii and Acanthamoeba spp. infections in the kidneys are not well known yet. Deeper knowledge of kidney involvement in leishmaniasis and malaria by presenting their mechanisms provides insight into how to create novel and effective treatments. Additionally, the presented work shows gaps in the pathophysiology of renal toxoplasmosis and acanthamoebiasis, which need further research.


Author(s):  
Chaoqun Yao

Abstract The kinetoplastid protozoan Leishmania spp. cause leishmaniasis, which clinically exhibit mainly as a cutaneous, mucocutanous or visceral form depending upon the parasite species in humans. The disease is widespread geographically, leading to 20 000 annual deaths. Here, leishmaniases in both humans and animals, reservoirs and sand fly vectors on the Caribbean islands are reviewed. Autochthonous human infections by Leishmania spp. were found in the Dominican Republic, Guadeloupe and Martinique as well as Trinidad and Tobago; canine infections were found in St. Kitts and Grenada; and equine infections were found in Puerto Rico. Imported human cases have been reported in Cuba. The parasites included Leishmania amazonensis, Le. martiniquensis and Le. waltoni. Possible sand fly vectors included Lutzomyia christophei, Lu. atroclavatus, Lu. cayennensis and Lu. flaviscutellata as well as Phlebotomus guadeloupensis. Reservoirs included rats, rice rats and mouse opossum. An updated study is warranted for the control and elimination of leishmaniasis in the region because some of the data are four decades old.


2021 ◽  
Author(s):  
Jari Zambarbieri ◽  
Claudio Pigoli ◽  
Mario Caniatti ◽  
Paola Scarpa
Keyword(s):  

2018 ◽  
Vol 38 (7) ◽  
pp. 1394-1404
Author(s):  
Lorena F. Silva ◽  
Guilherme R. Blume ◽  
Rômulo S.A. Eloi ◽  
Jaqueline A. Lemos ◽  
Anahí S. Silva ◽  
...  

RESUMO: Mãos e pés de cães são comumente afetados por lesões neoplásicas e não neoplásicas. Estas alterações podem apresentar prognóstico histopatológico ou clínico ruim e a amputação tende a ser o tratamento de escolha. Estudos prévios avaliando a prevalência e os aspectos clínicopatológicos de alterações digitais em cães têm sido realizados em outros países, entretanto trabalhos similares não foram realizados no Brasil. O objetivo do presente estudo foi descrever e caracterizar histologicamente as lesões das mãos e pés de cães. Amostras de 105 lesões tumoriformes das mãos e pés de cães foram avaliadas. Essas amostras foram coletadas entre 2003 e 2016 e foram obtidas de três laboratórios brasileiros de diagnóstico veterinário. Todos espécimes foram fixados em formol tamponado 10%, processados rotineiramente e corados por hematoxilina-eosina. Adicionalmente, as colorações de azul de toluidina, Brown e Breen, periodic acid Schiff (PAS), Grocott Methenamine Silver (GMS) e Ziehl Neelsen foram utilizados em casos específicos. Imuno-histoquímica foi realizada usando os anticorpos anti-Leishmania spp., anti-CD117, anti-CD79, anti-CD3, anti-Melan A, anti-lisozima, anti-Pancytokeratin AE1/AE3 e anti-vimentina. Os neoplasmas (62,9%) foram as alterações mais frequentes, seguidas por inflamações (19%) e outras alterações (18,1%). Entre os neoplasmas, 40,9% foram mesenquimais, 39,4% epiteliais e 19,7% de células redondas. Todos os neoplasmas de células redondas e a maioria dos epiteliais e mesenquimais eram malignos. Não se observou predileção de prevalência dos neoplasmas em relação ao sexo. As raças Labrador Retriever, Schnauzer, Teckel, SRD, Pastor Alemão, Rottweiler e Pit Bull foram as mais afetadas. Fila Brasileiro, Pit Bull e Schnauzer tiveram alta incidência de neoplasmas mesenquimais, epiteliais e de células redondas, respectivamente. Inflamação foi mais comumente observada em cães Labrador Retriever e as outras alterações em Teckel, Labrador Retriever e SRD. A idade e o peso médio dos animais afetados foram de 8,4 anos e 28,5 kg, respectivamente. O diâmetro médio das lesões tumoriformes foi de 2,5 cm e as lesões neoplásicas apresentaram as maiores médias. As lesões ocorreram principalmente em animais de pelagem amarela. A maioria das biópsias incisionais (56,4%) e amputações (85,3%) consistiram de neoplasmas. O principal membro afetado foi o torácico direito e o dígito foi a estrutura anatômica acometida mais frequentemente. Carcinoma de células escamosas (14,2%) foi o neoplasma mais frequente, seguido do mastocitoma (7,6%), melanoma (7,6%) e sarcoma indiferenciado (7,6%). Em metade dos casos de inflamação, a lesão acometeu o folículo piloso e derme adjacente, e o infiltrado foi predominantemente piogranulomatoso ou lnfoplasmocítico. Cistos foliculares, calcinose circunscrita e acrocordoma foram as principais lesões não neoplásicas e não inflamatórias diagnosticadas.


Sign in / Sign up

Export Citation Format

Share Document