In silico repositioning of etidronate as a potential inhibitor of the Trypanosoma cruzi enolase

Publication date: Available online 3 December 2019Source: Journal of Molecular Graphics and ModellingAuthor(s): Edward A. Valera-Vera, Melisa Sayé, Chantal Reigada, Mariana R. Miranda, Claudio A. PereiraAbstractEnolase is a glycolytic enzyme that catalyzes the interconversion between 2-phosphoglycerate and phosphoenolpyruvate. In trypanosomatids, enolase was proposed as a key enzyme after in silico and in vivo analysis and it was validated as a protein essential for the survival of the parasite. Therefore, enolase constitutes an interesting enzyme target for the identification of drugs against Chagas disease. In this work, a combined virtual screening strategy was implemented, employing similarity virtual screening, molecular docking, and molecular dynamics. First, two known enolase inhibitors and the enzyme substrates were used as queries for the similarity screening on the Sweetlead database using five different algorithms. Compounds retrieved in the top 10 of at least three search algorithms were selected for further analysis, resulting in six compounds of medical use (etidronate, pamidronate, fosfomycin, acetohydroxamate, triclofos, and aminohydroxybutyrate). Molecular docking simulations and pose re-scoring predicted that binding with acetohydroxamate and triclofos would be weak, while fosfomycin and aminohydroxybutyrate predicted binding is experimentally implausible. Docking poses obtained for etidronate, pamidronate, and PEP were used for molecular dynamics cal...
Source: Journal of Molecular Graphics and Modelling - Category: Molecular Biology Source Type: research

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Publication date: Available online 20 January 2020Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Oscar Campetella, Carlos A. Buscaglia, Juan Mucci, María Susana LeguizamónAbstractMany important pathogen-host interactions rely on highly specific carbohydrate binding events. In the case of the protozoan Trypanosoma cruzi, the causative agent of Chagas disease, glycointeractions involving sialic acid (SA) residues are pivotal for parasite infectivity, escape from immune surveillance and pathogenesis. Though unable to synthesize SA de novo, T. cruzi displays a unique trans-Sial...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research
Conclusions/SignificanceLoratadine, cyproheptadine and clofazimine inhibit TcAAAP069 proline transporter and also present trypanocidal effect against allT.cruzi life stages in strains from three different DTUs. These CV structural analogues could be a starting point to design therapeutic alternatives to treat Chagas disease by finding new indications for old drugs. This approach, called drug repurposing is a recommended strategy by the World Health Organization to treat neglected diseases, like Chagas disease, and combination therapy may improve the possibility of success of repositioned drugs.
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research
Triatomines are natural vectors of Chagas disease and are mainly prevalent in the Americas. In China, previous data from decades ago showed that there were two species of triatomine bugs, Triatoma rubrofasciata a...
Source: Parasites and Vectors - Category: Microbiology Authors: Tags: Research Source Type: research
Authors: Lizardo K, Ayyappan JP, Ganapathi U, Dutra WO, Qiu Y, Weiss LM, Nagajyothi JF Abstract Chagas disease is caused by Trypanosoma cruzi which is endemic in Latin America. T. cruzi infection results in a latent infection with approximately a third of latently infected patients developing chronic Chagas cardiomyopathy (CCM). CCM is a common cause of cardiomyopathy in endemic regions and has a poor prognosis compared to other cardiomyopathies. The factors responsible for the transition from the asymptomatic indeterminate latent stage of infection to CCM are poorly understood. Our previous studies demonstrated th...
Source: Disease Markers - Category: Laboratory Medicine Tags: Dis Markers Source Type: research
The etiological agent of Chagas disease, Trypanosoma cruzi, is an obligate intracellular parasite that infects an estimated 7 million people in the Americas, with an at-risk population of 70 million. Despite its recognition as the highest impact parasitic infection of the Americas, Chagas disease continues to receive insufficient attention and resources in order to be effectively combatted. Unlike the other parasitic trypanosomatids that infect humans (Trypanosoma brucei and Leishmania spp.), T. cruzi retains an ancestral mode of phagotrophic feeding via an endocytic organelle known as the cytostome-cytopharynx complex (SP...
Source: Frontiers in cellular and infection microbiology - Category: Microbiology Source Type: research
os Taylor Chagas disease, also known as American trypanosomiasis, is classified as a neglected disease by the World Health Organization. For clinical treatment, only two drugs have been on the market, Benznidazole and Nifurtimox, both of which are recommended for use in the acute phase but present low cure rates in the chronic phase. Furthermore, strong side effects may result in discontinuation of this treatment. Faced with this situation, we report the synthesis and trypanocidal activity of 3-benzoyl-flavanones. Novel 3-benzoyl-flavanone derivatives were prepared in satisfactory yields in the 3-step synthetic proc...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
Human B cells infected by Trypanosoma cruzi undergo F-actin disruption and cell death via caspase-7 activation and cleavage of phospholipase Cγ1. Immunobiology. 2020 Jan 16;:151904 Authors: Dos Santos MA, Alves Martins F, Borges BC, de Gouveia Santos J, Nascimento Alves R, Dias MH, BrígidoTavares PC, E Silva Brígido RT, Teixeira TL, Costa Rodrigues C, Cota Teixeira S, da Costa MS, da Silva AA, Barbosa Silva MJ, de Melo Rodrigues Ávila V, Patriarca Mineo TW, de Souza MA, Bahia D, da Silva CV Abstract B cells contribute to the immune system in many ways such as antigen present...
Source: Immunobiology - Category: Allergy & Immunology Authors: Tags: Immunobiology Source Type: research
This article is protected by copyright. All rights reserved. PMID: 31943572 [PubMed - as supplied by publisher]
Source: Cell Biology International - Category: Cytology Authors: Tags: Cell Biol Int Source Type: research
Authors: Norman FF, Comeche B, Chamorro S, López-Vélez R Abstract Introduction: Recent increases in population movements have created novel health challenges in many areas of the World, and health policies have been adapted accordingly in several countries. However, screening guidelines for infectious diseases are not standardized and generally do not include comprehensive screening for parasitic infections.Areas covered: Malaria, Chagas disease, leishmaniasis, amebiasis, filariases, strongyloidiasis and schistosomiasis are reviewed, focusing on the challenges posed for their diagnosis and management ...
Source: Expert Review of Anti-Infective Therapy - Category: Infectious Diseases Tags: Expert Rev Anti Infect Ther Source Type: research
Chagas disease is caused by Trypanosoma cruzi infection and represents an important public health concern in Latin America. Macrophages are one of the main infiltrating leukocytes in response to infection. Parasite persistence could trigger a sustained activation of these cells, contributing to the damage observed in this pathology, particularly in the heart. HP24, a pyridinecarboxylic acid derivative, is a new PPARγ ligand that exerts anti-inflammatory and pro-angiogenic effects. The aim of this work was to deepen the study of the mechanisms involved in the pro-angiogenic and anti-inflammatory effects of HP24 in T. ...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
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