scholarly journals Novel drug design for Chagas disease via targeting Trypanosoma cruzi tubulin: Homology modeling and binding pocket prediction on Trypanosoma cruzi tubulin polymerization inhibition by naphthoquinone derivatives

2016 ◽  
Vol 24 (16) ◽  
pp. 3849-3855 ◽  
Author(s):  
Charles O. Ogindo ◽  
Mozna H. Khraiwesh ◽  
Matthew George ◽  
Yakini Brandy ◽  
Nailah Brandy ◽  
...  
Keyword(s):  
Drug Design ◽  
Trypanosoma Cruzi ◽  
Homology Modeling ◽  
Chagas Disease ◽  
Binding Pocket ◽  
Tubulin Polymerization ◽  
Novel Drug ◽  
Pocket Prediction

scholarly journals Cruzain structures: apocruzain and cruzain bound to S-methyl thiomethanesulfonate and implications for drug design

2019 ◽  
Vol 75 (6) ◽  
pp. 419-427 ◽  
Author(s):  
Elany Barbosa da Silva ◽  
Elfriede Dall ◽  
Peter Briza ◽  
Hans Brandstetter ◽  
Rafaela Salgado Ferreira
Keyword(s):  
Drug Design ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Cysteine Protease ◽  
In Silico ◽  
Structural Information ◽  
Mass Spectrometric ◽  
Catalytic Cysteine ◽  
Reversible Covalent ◽  
Covalent Inhibitor

Chagas disease, which is caused by Trypanosoma cruzi, affects more than six million people worldwide. Cruzain is the major cysteine protease involved in the survival of this parasite. Here, the expression, purification and crystallization of this enzyme are reported. The cruzain crystals diffracted to 1.2 Å resolution, yielding two novel cruzain structures: apocruzain and cruzain bound to the reversible covalent inhibitor S-methyl thiomethanesulfonate. Mass-spectrometric experiments confirmed the presence of a methylthiol group attached to the catalytic cysteine. Comparison of these structures with previously published structures indicates the rigidity of the cruzain structure. These results provide further structural information about the enzyme and may help in new in silico studies to identify or optimize novel prototypes of cruzain inhibitors.

Dynamics of T Cells Repertoire During Trypanosoma cruzi Infection and its Post-Treatment Modulation

2019 ◽  
Vol 26 (36) ◽  
pp. 6519-6543 ◽  
Author(s):  
Adriana Egui ◽  
Paola Lasso ◽  
Elena Pérez-Antón ◽  
M. Carmen Thomas ◽  
Manuel Carlos López
Keyword(s):  
Immune Response ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Cardiac Tissue ◽  
Acute Infection ◽  
Clinical Status ◽  
Chronic Phase ◽  
Parasite Load ◽  
Chronic Patients ◽  
Cruzi Infection

Chagas disease courses with different clinical phases and has a variable clinical presentation and progression. The acute infection phase mostly exhibits a non-specific symptomatology. In the absence of treatment, the acute phase is followed by a chronic phase, which is initially asymptomatic. This chronic asymptomatic phase of the disease is characterized by a fragile balance between the host’s immune response and the parasite replication. The loss of this balance is crucial for the progression of the sickness. The virulence and tropism of the T. cruzi infecting strain together to the inflammation processes in the cardiac tissue are the main factors for the establishment and severity of the cardiomyopathy. The efficacy of treatment in chronic Chagas disease patients is controversial. However, several studies carried out in chronic patients demonstrated that antiparasitic treatment reduces parasite load in the bloodstream and leads to an improvement in the immune response against the Trypanosoma cruzi parasite. The present review is mainly focused on the cellular patterns associated to the clinical status and the evolution of the disease in chronic patients, as well as the effectiveness of the treatment related to T. cruzi infection control. Therefore, an emphasis is placed on the dynamics of specific-antigens T cell subpopulations, their memory and activation phenotypes, their functionality and their contribution to pathogenesis or disease control, as well as their association with risk of congenital transmission of the parasite.

The Prevalence of Trypanosoma cruzi, the Causal Agent of Chagas Disease, in Texas Rodent Populations

EcoHealth ◽  
2017 ◽  
Vol 14 (1) ◽  
pp. 130-143 ◽  
Author(s):  
Adriana Aleman ◽  
Trina Guerra ◽  
Troy J. Maikis ◽  
Matthew T. Milholland ◽  
Ivan Castro-Arellano ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Causal Agent ◽  
Rodent Populations

scholarly journals Absence of Bim sensitizes mice to experimental Trypanosoma cruzi infection

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Marcela Hernández-Torres ◽  
Rogério Silva do Nascimento ◽  
Monica Cardozo Rebouças ◽  
Alexandra Cassado ◽  
Kely Catarine Matteucci ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Parasite Load ◽  
Peritoneal Macrophages ◽  
T Cell Response ◽  
No Production ◽  
Similar Reduction ◽  
Ifn Γ

AbstractChagas disease is a life-threatening disorder caused by the protozoan parasite Trypanosoma cruzi. Parasite-specific antibodies, CD8+ T cells, as well as IFN-γ and nitric oxide (NO) are key elements of the adaptive and innate immunity against the extracellular and intracellular forms of the parasite. Bim is a potent pro-apoptotic member of the Bcl-2 family implicated in different aspects of the immune regulation, such as negative selection of self-reactive thymocytes and elimination of antigen-specific T cells at the end of an immune response. Interestingly, the role of Bim during infections remains largely unidentified. To explore the role of Bim in Chagas disease, we infected WT, Bim+/−, Bim−/− mice with trypomastigotes forms of the Y strain of T. cruzi. Strikingly, our data revealed that Bim−/− mice exhibit a delay in the development of parasitemia followed by a deficiency in the control of parasite load in the bloodstream and a decreased survival compared to WT and Bim+/− mice. At the peak of parasitemia, peritoneal macrophages of Bim−/− mice exhibit decreased NO production, which correlated with a decrease in the pro-inflammatory Small Peritoneal Macrophage (SPM) subset. A similar reduction in NO secretion, as well as in the pro-inflammatory cytokines IFN-γ and IL-6, was also observed in Bim−/− splenocytes. Moreover, an impaired anti-T. cruzi CD8+ T-cell response was found in Bim−/− mice at this time point. Taken together, our results suggest that these alterations may contribute to the establishment of a delayed yet enlarged parasitic load observed at day 9 after infection of Bim−/− mice and place Bim as an important protein in the control of T. cruzi infections.

scholarly journals Complete Inactivation of Blood Borne Pathogen Trypanosoma cruzi in Stored Human Platelet Concentrates and Plasma Treated With 405 nm Violet-Blue Light

2020 ◽  
Vol 7 ◽  
Author(s):  
Katarzyna I. Jankowska ◽  
Rana Nagarkatti ◽  
Nirmallya Acharyya ◽  
Neetu Dahiya ◽  
Caitlin F. Stewart ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Human Plasma ◽  
Blue Light ◽  
Chagas Disease ◽  
Light Treatment ◽  
Platelet Concentrates ◽  
Complete Inactivation ◽  
Pathogen Reduction ◽  
Biochemical Indices

The introduction of pathogen reduction technologies (PRTs) to inactivate bacteria, viruses and parasites in donated blood components stored for transfusion adds to the existing arsenal toward reducing the risk of transfusion-transmitted infectious diseases (TTIDs). We have previously demonstrated that 405 nm violet-blue light effectively reduces blood-borne bacteria in stored human plasma and platelet concentrates. In this report, we investigated the microbicidal effect of 405 nm light on one important bloodborne parasite Trypanosoma cruzi that causes Chagas disease in humans. Our results demonstrated that a light irradiance at 15 mWcm−2 for 5 h, equivalent to 270 Jcm−2, effectively inactivated T. cruzi by over 9.0 Log10, in plasma and platelets that were evaluated by a MK2 cell infectivity assay. Giemsa stained T. cruzi infected MK2 cells showed that the light-treated parasites in plasma and platelets were deficient in infecting MK2 cells and did not differentiate further into intracellular amastigotes unlike the untreated parasites. The light-treated and untreated parasite samples were then evaluated for any residual infectivity by injecting the treated parasites into Swiss Webster mice, which did not develop infection even after the animals were immunosuppressed, further demonstrating that the light treatment was completely effective for inactivation of the parasite; the light-treated platelets had similar in vitro metabolic and biochemical indices to that of untreated platelets. Overall, these results provide a proof of concept toward developing 405 nm light treatment as a pathogen reduction technology (PRT) to enhance the safety of stored human plasma and platelet concentrates from bloodborne T. cruzi, which causes Chagas disease.

scholarly journals Chemical Validation of Phosphodiesterase C as a Chemotherapeutic Target in Trypanosoma cruzi, the Etiological Agent of Chagas' Disease

2010 ◽  
Vol 54 (9) ◽  
pp. 3738-3745 ◽  
Author(s):  
Sharon King-Keller ◽  
Minyong Li ◽  
Alyssa Smith ◽  
Shilong Zheng ◽  
Gurpreet Kaur ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Catalytic Domain ◽  
Polypeptide Chain ◽  
Inflammatory Diseases ◽  
New Drugs ◽  
Volume Recovery ◽  
Chronic Pulmonary Diseases ◽  
Potential Inhibitors

ABSTRACT Trypanosoma cruzi phosphodiesterase (PDE) C (TcrPDEC), a novel and rather unusual PDE in which, unlike all other class I PDEs, the catalytic domain is localized in the middle of the polypeptide chain, is able to hydrolyze cyclic GMP (cGMP), although it prefers cyclic AMP (cAMP), and has a FYVE-type domain in its N-terminal region (S. Kunz et al., FEBS J. 272:6412-6422, 2005). TcrPDEC shows homology to the mammalian PDE4 family members. PDE4 inhibitors are currently under development for the treatment of inflammatory diseases, such as asthma, chronic pulmonary diseases, and psoriasis, and for treating depression and serving as cognitive enhancers. We therefore tested a number of compounds originally synthesized as potential PDE4 inhibitors on T. cruzi amastigote growth, and we obtained several useful hits. We then conducted homology modeling of T. cruzi PDEC and identified other compounds as potential inhibitors through virtual screening. Testing of these compounds against amastigote growth and recombinant TcrPDEC activity resulted in several potent inhibitors. The most-potent inhibitors were found to increase the cellular concentration of cAMP. Preincubation of cells in the presence of one of these compounds stimulated volume recovery after hyposmotic stress, in agreement with their TcrPDEC inhibitory activity in vitro, providing chemical validation of this target. The compounds found could be useful tools in the study of osmoregulation in T. cruzi. In addition, their further optimization could result in the development of new drugs against Chagas' disease and other trypanosomiases.

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