scholarly journals Mechanism of Action of 4-Phenoxyphenoxyethyl Thiocyanate (WC-9) against Trypanosoma cruzi, the Causative Agent of Chagas’ Disease

2003 ◽  
Vol 47 (6) ◽  
pp. 2047-2050 ◽  
Author(s):  
Julio A. Urbina ◽  
Juan Luis Concepcion ◽  
Andrea Montalvetti ◽  
Juan B. Rodriguez ◽  
Roberto Docampo
Keyword(s):  
Trypanosoma Cruzi ◽  
Growth Inhibition ◽  
Chagas Disease ◽  
Causative Agent ◽  
Mechanism Of Action ◽  
Molecular Basis ◽  
De Novo ◽  
Squalene Synthase ◽  
Etiological Agent ◽  
De Novo Synthesis

ABSTRACT We investigated the molecular basis of the activity of 4-phenoxyphenoxyethyl thiocyanate (WC-9) against Trypanosoma cruzi, the etiological agent of Chagas’ disease. We found that growth inhibition of T. cruzi epimastigotes induced by this compound was associated with a reduction in the content of the parasite's endogenous sterols due to a specific blockade of their de novo synthesis at the level of squalene synthase.

scholarly journals In Vitro and In Vivo Activities of E5700 and ER-119884, Two Novel Orally Active Squalene Synthase Inhibitors, against Trypanosoma cruzi

2004 ◽  
Vol 48 (7) ◽  
pp. 2379-2387 ◽  
Author(s):  
Julio A. Urbina ◽  
Juan Luis Concepcion ◽  
Aura Caldera ◽  
Gilberto Payares ◽  
Cristina Sanoja ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Public Health Problem ◽  
Squalene Synthase ◽  
Host Cells ◽  
In Vivo Studies ◽  
Inorganic Pyrophosphate ◽  
Orally Active

ABSTRACT Chagas' disease is a serious public health problem in Latin America, and no treatment is available for the prevalent chronic stage. Its causative agent, Trypanosoma cruzi, requires specific endogenous sterols for survival, and we have recently demonstrated that squalene synthase (SQS) is a promising target for antiparasitic chemotherapy. E5700 and ER-119884 are quinuclidine-based inhibitors of mammalian SQS that are currently in development as cholesterol- and triglyceride-lowering agents in humans. These compounds were found to be potent noncompetitive or mixed-type inhibitors of T. cruzi SQS with K i values in the low nanomolar to subnanomolar range in the absence or presence of 20 μM inorganic pyrophosphate. The antiproliferative 50% inhibitory concentrations of the compounds against extracellular epimastigotes and intracellular amastigotes were ca. 10 nM and 0.4 to 1.6 nM, respectively, with no effects on host cells. When treated with these compounds at the MIC, all of the parasite's sterols disappeared from the parasite cells. In vivo studies indicated that E5700 was able to provide full protection against death and completely arrested the development of parasitemia when given at a concentration of 50 mg/kg of body weight/day for 30 days, while ER-119884 provided only partial protection. This is the first report of an orally active SQS inhibitor that is capable of providing complete protection against fulminant, acute Chagas' disease.

scholarly journals Human T-cell lymphotropic virus type I-transformed T-cells have a partial defect in ceramide synthesis in response to N-(4-hydroxyphenyl)retinamide

2005 ◽  
Vol 392 (1) ◽  
pp. 231-239 ◽  
Author(s):  
Nadine Darwiche ◽  
Ghada Abou-Lteif ◽  
Tarek Najdi ◽  
Lina Kozhaya ◽  
Ahmad Abou Tayyoun ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Inhibition ◽  
Virus Type ◽  
De Novo ◽  
Type I ◽  
De Novo Synthesis ◽  
Human T Cell ◽  
Ceramide Synthesis ◽  
Malignant T Cells

Treatment with the synthetic retinoid HPR [N-(4-hydroxyphenyl)-retinamide] causes growth arrest and apoptosis in HTLV-I (human T-cell lymphotropic virus type-I)-positive and HTLV-I-negative malignant T-cells [8]. It was observed that HPR-mediated growth inhibition was associated with ceramide accumulation only in HTLV-I-negative cells. The aim of the present study was to investigate the mechanism by which HPR differentially regulates ceramide metabolism in HTLV-I-negative and HTLV-I-positive malignant T-cells. Clinically achievable concentrations of HPR caused early dose-dependent increases in ceramide levels only in HTLV-I-negative cells and preceded HPR-induced growth suppression. HPR induced de novo synthesis of ceramide in HTLV-I-negative, but not in HTLV-I-positive, cells. Blocking ceramide glucosylation in HTLV-I-positive cells, which leads to accumulation of endogenous ceramide, rendered these cells more sensitive to HPR. Exogenous cell-permeant ceramides that function partially by generating endogenous ceramide induced growth suppression in all tested malignant lymphocytes, were consistently found to be less effective in HTLV-I-positive cells confirming their defect in de novo ceramide synthesis. Owing to its multipotent activities, the HTLV-I-encoded Tax protein was suspected to inhibit ceramide synthesis. Tax-transfected Molt-4 and HELA cells were less sensitive to HPR and C6-ceramide mediated growth inhibition respectively and produced lower levels of endogenous ceramide. Together, these results indicate that HTLV-I-positive cells are defective in de novo synthesis of ceramide and that therapeutic modalities that bypass this defect are more likely to be successful.

A novel triazolic naphthofuranquinone induces autophagy in reservosomes and impairment of mitosis in Trypanosoma cruzi

Parasitology ◽  
2011 ◽  
Vol 139 (1) ◽  
pp. 26-36 ◽  
Author(s):  
M. C. FERNANDES ◽  
E. N. DA SILVA ◽  
A. V. PINTO ◽  
S. L. DE CASTRO ◽  
R. F. S. MENNA-BARRETO
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Mechanism Of Action ◽  
Folk Medicine ◽  
Flow Cytometric Analysis ◽  
Inhibitory Effect ◽  
Membrane Structures ◽  
Starting Point ◽  
Nitro Derivatives ◽  
Good Starting Point

SUMMARYChagas' disease, caused by the protozoan Trypanosoma cruzi, represents a serious health problem in Latin America, and the available chemotherapy, which is based on 2 nitro-derivatives, is not satisfactory. In folk medicine, natural products including naphthoquinones have been employed for the treatment of different parasitic diseases. In the pursuit of alternative drugs for Chagas' disease, we investigated the mechanism of action of the triazolic naphthoquinone (TN; 2,2-dimethyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2,3-dihydronaphtho[1,2-b]furan-4,5-dione), which is the most active compound against T. cruzi trypomastigotes among a series of naphthofuranquinones. TN was active against the 3 parasite forms producing a dose-dependent inhibitory effect. In epimastigotes, TN induced reservosome disruption, flagellar blebbing, Golgi disorganization, the presence of cytosolic concentric membrane structures and abnormal multiflagellar parasites. The treatment also led to the appearance of well-developed endoplasmic reticulum profiles surrounding organelles that associated with an increase in monodansylcadaverine labelling, suggesting autophagy as part of the TN mechanism of action. Interestingly, no ultrastructural damage was detected in the mitochondria of naphthoquinone-treated epimastigotes. Flow cytometric analysis demonstrated an impairment of mitosis, an increase in ROS production and the maintenance of mitochondrial membrane potential. TN could be a good starting point in the investigation of a chemotherapeutic approach for the treatment of Chagas' disease.

scholarly journals Trypanosoma cruzi Phosphomannomutase and Guanosine Diphosphate-Mannose Pyrophosphorylase Ligandability Assessment

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Filip Zmuda ◽  
Sharon M. Shepherd ◽  
Michael A. J. Ferguson ◽  
David W. Gray ◽  
Leah S. Torrie ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cell Surface ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
De Novo ◽  
Chemical Space ◽  
Nucleotide Sugar ◽  
Content Type ◽  
Life Cycle Stages ◽  
Drug Discovery Program

ABSTRACT Chagas’ disease, which is caused by the Trypanosoma cruzi parasite, has become a global health problem that is currently treated with poorly tolerated drugs that require prolonged dosing. Therefore, there is a clinical need for new therapeutic agents that can mitigate these issues. The phosphomannomutase (PMM) and GDP-mannose pyrophosphorylase (GDP-MP) enzymes form part of the de novo biosynthetic pathway to the nucleotide sugar GDP-mannose. This nucleotide sugar is used either directly, or indirectly via the formation of dolichol-phosphomannose, for the assembly of all mannose-containing glycoconjugates. In T. cruzi, mannose-containing glycoconjugates include the cell-surface glycoinositol-phospholipids and the glycosylphosphatidylinositol-anchored mucin-like glycoproteins that dominate the cell surface architectures of all life cycle stages. This makes PMM and GDP-MP potentially attractive targets for a drug discovery program against Chagas’ disease. To assess the ligandability of these enzymes in T. cruzi, we have screened 18,117 structurally diverse compounds exploring drug-like chemical space and 16,845 small polar fragment compounds using an assay interrogating the activities of both PMM and GDP-MP enzymes simultaneously. This resulted in 48 small fragment hits, and on retesting 20 were found to be active against the enzymes. Deconvolution revealed that these were all inhibitors of T. cruzi GDP-MP, with compounds 2 and 3 acting as uncompetitive and competitive inhibitors, respectively. Based on these findings, the T. cruzi PMM and GDP-MP enzymes were deemed not ligandable and poorly ligandable, respectively, using small molecules from conventional drug discovery chemical space. This presents a significant hurdle to exploiting these enzymes as therapeutic targets for Chagas’ disease.

scholarly journals Dispersal patterns of Trypanosoma cruzi in Arequipa, Peru

2019 ◽  
Author(s):  
Alexander S.F. Berry ◽  
Renzo Salazar-Sánchez ◽  
Ricardo Castillo-Neyra ◽  
Katty Borrini-Mayorí ◽  
Claudia Arevalo-Nieto ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Causative Agent ◽  
Animal Movement ◽  
Protozoan Parasite ◽  
Domestic Animal ◽  
Urban Environments ◽  
Urban Landscapes ◽  
Population Genomic ◽  
The City

AbstractAnthropogenic environmental alterations such as urbanization can threaten native populations as well as create novel environments that allow human pests and pathogens to thrive. As the number and size of urban environments increase globally, it is more important than ever to understand the dispersal dynamics of hosts, vectors and pathogens of zoonotic disease systems. For example, a protozoan parasite and the causative agent of Chagas disease in humans, Trypanosoma cruzi, recently colonized and spread through the city of Arequipa, Peru. We used population genomic and phylogenomic tools to analyze whole genomes of 123 T. cruzi isolates collected throughout Arequipa to determine patterns of T. cruzi dispersal. The data show significant population genetic structure within city blocks-parasites in the same block tend to be very closely related - but no population structure among blocks within districts - parasites in neighboring blocks are no more closely related to one another than to parasites in distant districts. These data suggest that T. cruzi dispersal within a block occurs regularly and that occasional long-range dispersal events allow the establishment of new T. cruzi populations in distant blocks. Movement of domestic animals may be the primary mechanism of inter-block and inter-district T. cruzi dispersal.Author SummaryUrbanization creates environments that are ideal for some human pests and pathogens. As the number and size of urban environments increases globally, it is becoming vital to understand how human disease-causing pathogens, their vectors, and their non-human hosts disperse through urban landscapes. Here we study a population of Trypanosoma cruzi – the protozoan parasite and causative agent of Chagas disease in humans – that recently colonized the city of Arequipa, Peru. We use population genomic and phylogenomic tools to understand how this parasite population dispersed through the city to achieve its current distribution and abundance. We show that T. cruzi collected from the same city block tend to be very closely related, while those from neighboring blocks are often as distantly related as those from blocks in distant districts. The data suggest that vectors facilitate frequent within-block dispersal of the parasite, while domestic animal movement may facilitate the relatively infrequent inter-block and interdistrict dispersal.

scholarly journals Discovery and Optimization of a Compound Series Active against Trypanosoma cruzi, the Causative Agent of Chagas Disease

2020 ◽  
Vol 63 (6) ◽  
pp. 3066-3089
Author(s):  
Justin R. Harrison ◽  
Sandipan Sarkar ◽  
Shahienaz Hampton ◽  
Jennifer Riley ◽  
Laste Stojanovski ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Causative Agent ◽  
Compound Series

Comparative high-throughput analysis of the Trypanosoma cruzi response to organometallic compounds

Metallomics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 813-828
Author(s):  
M. Florencia Mosquillo ◽  
Pablo Smircich ◽  
Martín Ciganda ◽  
Analía Lima ◽  
Dinorah Gambino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Trypanosoma Cruzi ◽  
Expression Pattern ◽  
Chagas Disease ◽  
High Throughput ◽  
Causative Agent ◽  
Gene Expression Pattern ◽  
Organometallic Compounds ◽  
Global Gene Expression ◽  
High Throughput Analysis

An in-depth, comparative look at the effects of two structurally related organometallic Pd and Pt compounds on the global gene expression pattern of T. cruzi epimastigotes. This parasite is the causative agent of Chagas disease.

Proteome analysis of the causative agent of Chagas disease: Trypanosoma cruzi

2004 ◽  
Vol 34 (8) ◽  
pp. 881-886 ◽  
Author(s):  
Adriana Parodi-Talice ◽  
Rosario Durán ◽  
Nicolás Arrambide ◽  
Victoria Prieto ◽  
Marı́a Dolores Piñeyro ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Causative Agent ◽  
Proteome Analysis

scholarly journals Identification of a proteasome-targeting arylsulfonamide with potential for the treatment of Chagas’ disease

2021 ◽  
Author(s):  
Marta Lima ◽  
Lindsay B Tulloch ◽  
Victoriano Corpas-Lopez ◽  
Sandra Carvalho ◽  
Richard J. Wall ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Causative Agent ◽  
Mode Of Action ◽  
Malic Enzyme ◽  
Proteasome Inhibitors ◽  
Genetically Engineered ◽  
Phenotypic Screening

Phenotypic screening identified an arylsulfonamide compound with activity against Trypanosoma cruzi , the causative agent of Chagas’ disease. Comprehensive mode of action studies revealed that this compound primarily targets the T. cruzi proteasome, binding at the interface between β4 and β5 subunits that catalyse chymotrypsin-like activity. A mutation in the β5 subunit of the proteasome was associated with resistance to compound 1 , while overexpression of this mutated subunit also reduced susceptibility to compound 1 . Further genetically engineered and in vitro selected clones resistant to proteasome inhibitors known to bind at the β4/β5 interface were cross-resistant to compound 1 . Ubiquitinylated proteins were additionally found to accumulate in compound 1 -treated epimastigotes. Finally, thermal proteome profiling identified malic enzyme as a secondary target of compound 1 , although malic enzyme inhibition was not found to drive potency. These studies identify a novel pharmacophore capable of inhibiting the T. cruzi proteasome that may be exploitable for anti-chagasic drug discovery.

Kindling, Logs, and Coals: The Dynamics of Trypanosoma cruzi, the Etiological Agent of Chagas Disease in Arequipa, Peru

2020 ◽  
pp. 215-226
Author(s):  
Michael Z. Levy
Keyword(s):  
Trypanosoma Cruzi ◽  
Salivary Glands ◽  
Chagas Disease ◽  
Etiologic Agent ◽  
Etiological Agent ◽  
Insect Vector ◽  
Blood Sucking ◽  
Vector Borne ◽  
Triatomine Insects

The forces that lead to the emergence of Trypanosoma cruzi, the etiologic agent of Chagas disease, are often distinct from those that maintain its transmission, and these are distinct again from those that allow the parasite to persist over decades. Just as kindling, logs, and coals all play discrete roles in the growth of a fire, a myriad of mammalian hosts contribute differently to epidemics of Trypanosoma. cruzi. Chagas disease affects millions of people in the Americas, and, through migration, thousands more on other continents. The agent of the disease, Trypanosoma cruzi, is a slender, highly-motile, unicellular parasite. T. cruzi does not migrate to the salivary glands of its insect vector–the blood-sucking triatomine insects–as many other vector-borne parasites do.

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