scholarly journals Lipophilic Antifolate Trimetrexate Is a Potent Inhibitor of Trypanosoma cruzi: Prospect for Chemotherapy of Chagas' Disease

2005 ◽  
Vol 49 (8) ◽  
pp. 3234-3238 ◽  
Author(s):  
Olga Senkovich ◽  
Vandanajay Bhatia ◽  
Nisha Garg ◽  
Debasish Chattopadhyay
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Dihydrofolate Reductase ◽  
Drug Target ◽  
Potent Inhibitor ◽  
Pneumocystis Carinii ◽  
Lethal Dose ◽  
Public Health Problem ◽  
Protozoan Parasite ◽  
Track Record

ABSTRACT Trypanosoma cruzi, a protozoan parasite, is the causative agent for Chagas' disease, which poses serious public health problem in Latin America. The two drugs available for the treatment of this disease are effective only against recent infections and are toxic. Dihydrofolate reductase (DHFR) has a proven track record as a drug target. The lipophilic antifolate trimetrexate (TMQ), which is an FDA-approved drug for the treatment of Pneumocystis carinii infection in AIDS patients, is a potent inhibitor of T. cruzi DHFR activity, with an inhibitory constant of 6.6 nM. The compound is also highly effective in killing T. cruzi parasites. The 50 and 90% lethal dose values against the trypomastigote are 19 and 36 nM, and the corresponding values for the amastigote form are 26 and 72 nM, respectively. However, as TMQ is also a good inhibitor of human DHFR, further improvement of the selectivity of this drug would be preferable. Identification of a novel antifolate selective against T. cruzi would open up new therapeutic avenues for treatment of Chagas' disease.

scholarly journals Identification of Inhibitors to Trypanosoma cruzi Sirtuins Based on Compounds Developed to Human Enzymes

2020 ◽  
Vol 21 (10) ◽  
pp. 3659
Author(s):  
Tanira Matutino Bastos ◽  
Milena Botelho Pereira Soares ◽  
Caio Haddad Franco ◽  
Laura Alcântara ◽  
Lorenzo Antonini ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Mammalian Cells ◽  
Drug Target ◽  
Drug Targets ◽  
Synergistic Effects ◽  
Protozoan Parasite ◽  
Disease Treatment ◽  
Specific Parasite ◽  
Specific Inhibitors

Chagas disease is an illness caused by the protozoan parasite Trypanosoma cruzi, affecting more than 7 million people in the world. Benznidazole and nifurtimox are the only drugs available for treatment and in addition to causing several side effects, are only satisfactory in the acute phase of the disease. Sirtuins are NAD+-dependent deacetylases involved in several biological processes, which have become drug target candidates in various disease settings. T. cruzi presents two sirtuins, one cytosolic (TcSir2rp1) and the latter mitochondrial (TcSir2rp3). Here, we characterized the effects of human sirtuin inhibitors against T. cruzi sirtuins as an initial approach to develop specific parasite inhibitors. We found that, of 33 compounds tested, two inhibited TcSir2rp1 (15 and 17), while other five inhibited TcSir2rp3 (8, 12, 13, 30, and 32), indicating that specific inhibitors can be devised for each one of the enzymes. Furthermore, all inhibiting compounds prevented parasite proliferation in cultured mammalian cells. When combining the most effective inhibitors with benznidazole at least two compounds, 17 and 32, demonstrated synergistic effects. Altogether, these results support the importance of exploring T. cruzi sirtuins as drug targets and provide key elements to develop specific inhibitors for these enzymes as potential targets for Chagas disease treatment.

scholarly journals MicroRNA-155 Deficiency Exacerbates Trypanosoma cruzi Infection

2020 ◽  
Vol 88 (7) ◽  
Author(s):  
Bijay K. Jha ◽  
Sanjay Varikuti ◽  
Gabriella R. Seidler ◽  
Greta Volpedo ◽  
Abhay R. Satoskar ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Public Health Problem ◽  
Protozoan Parasite ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Inflammatory Monocytes ◽  
Nk T Cells

ABSTRACT Chagas disease, caused by the intracellular protozoan parasite Trypanosoma cruzi, is a public health problem affecting 6 to 8 million people, mainly in Latin America. The role of microRNAs in the pathogenesis of Chagas disease has not been well described. Here, we investigate the role of microRNA-155 (miR-155), a proinflammatory host innate immune regulator responsible for T helper type 1 and type 17 (Th1 and Th17) development and macrophage responses during T. cruzi infection. For this, we compared the survival and parasite growth and distribution in miR-155−/− and wild-type (WT) C57BL/6 mice. The lack of miR-155 caused robust parasite infection and diminished survival of infected mice, while WT mice were resistant to infection. Immunological analysis of infected mice indicated that, in the absence of miR-155, there was decreased interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. In addition, we found that there was a significant reduction of CD8-positive (CD8+) T cells, natural killer (NK) cells, and NK-T cells and increased accumulation of neutrophils and inflammatory monocytes in miR-155−/− mice. Collectively, these data indicate that miR-155 is an important immune regulatory molecule critical for the control of T. cruzi infection.

Temperature, Mitochondria, and Reye's Syndrome

PEDIATRICS ◽  
1983 ◽  
Vol 71 (6) ◽  
pp. 985-985
Author(s):  
RIF S. EL-MALLAKH
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Protozoan Parasite ◽  
Mitochondrial Enzyme ◽  
Reye's Syndrome ◽  
Electron Microscopic ◽  
Microscopic Studies ◽  
Mitochondrial Defect ◽  
Intracellular Protozoan Parasite

To the Editor.— Mitochondrial failure, manifest by changes in mitochondrial enzyme activity1-3 and morphology,4-5 is central to Reye's syndrome (RS).6 Although it has been variously hypothesized that the mitochondrial changes are secondary to an exogenous toxin,7-12 or an intrinsic mitochondrial defect,6 the actual cause remains obscure. Electron microscopic studies have shown sweelling and loss of cristate in mitochondria of patients with RS. It is interesting that very similar changes occur in Trypanosoma cruzi.13-16 T cruzi is an extracellular/intracellular protozoan parasite which causes Chagas' disease.17

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 Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Solange L. de Castro ◽  
Denise G. J. Batista ◽  
Marcos M. Batista ◽  
Wanderson Batista ◽  
Anissa Daliry ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Chronic Phase ◽  
Public Health Problem ◽  
Term Therapy ◽  
High Morbidity ◽  
Synthetic Compounds ◽  
Natural And Synthetic

Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately eight million individuals in Latin America and is emerging in nonendemic areas due to the globalisation of immigration and nonvectorial transmission routes. Although CD represents an important public health problem, resulting in high morbidity and considerable mortality rates, few investments have been allocated towards developing novel anti-T. cruzi agents. The available therapy for CD is based on two nitro derivatives (benznidazole (Bz) and nifurtimox (Nf)) developed more than four decades ago. Both are far from ideal due to substantial secondary side effects, limited efficacy against different parasite isolates, long-term therapy, and their well-known poor activity in the late chronic phase. These drawbacks justify the urgent need to identify better drugs to treat chagasic patients. Although several classes of natural and synthetic compounds have been reported to act in vitro and in vivo on T. cruzi, since the introduction of Bz and Nf, only a few drugs, such as allopurinol and a few sterol inhibitors, have moved to clinical trials. This reflects, at least in part, the absence of well-established universal protocols to screen and compare drug activity. In addition, a large number of in vitro studies have been conducted using only epimastigotes and trypomastigotes instead of evaluating compounds' activities against intracellular amastigotes, which are the reproductive forms in the vertebrate host and are thus an important determinant in the selection and identification of effective compounds for further in vivo analysis. In addition, due to pharmacokinetics and absorption, distribution, metabolism, and excretion characteristics, several compounds that were promising in vitro have not been as effective as Nf or Bz in animal models of T. cruzi infection. In the last two decades, our team has collaborated with different medicinal chemistry groups to develop preclinical studies for CD and investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi.

Development of new dinuclear Fe(III) coordination compounds with in vitro nanomolar antitrypanosomal activity

2021 ◽  
Author(s):  
Felipe Figuerôa Moreira ◽  
Juliana de Araujo Portes ◽  
Nathalia Florencia Barros Azeredo ◽  
Christiane Fernandes ◽  
Adolfo Horn ◽  
...  
Keyword(s):  
Public Health ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Health Problem ◽  
Coordination Compounds ◽  
Public Health Problem ◽  
Neglected Tropical Disease ◽  
Major Public Health Problem ◽  
Protozoan Pathogen

Chagas disease is a neglected tropical disease caused by the protozoan pathogen Trypanosoma cruzi. The disease is the major public health problem affecting about 6 to 7 million people worldwide,...

Lipid biosynthesis pathways as chemotherapeutic targets in kinetoplastid parasites

Parasitology ◽  
1997 ◽  
Vol 114 (7) ◽  
pp. 91-99 ◽  
Author(s):  
J. A. URBINA
Keyword(s):  
Trypanosoma Cruzi ◽  
Recent Work ◽  
Chagas Disease ◽  
Pneumocystis Carinii ◽  
Lipid Biosynthesis ◽  
Sterol Biosynthesis ◽  
Leishmania Braziliensis ◽  
Biosynthesis Inhibitors

Inhibitors of sterol and phospholipid biosynthesis in kinetoplastid parasites such as Trypanosoma cruzi, the causative agent of Chagas' disease, and different species of Leishmania have potent and selective activity as chemotherapeutic agents in vitro and in vivo. Recent work with the sterol C14α-demethylase inhibitor D0870, a bis triazole derivative, showed that this compound is capable of inducing radical parasitological cure in murine models of both acute and chronic Chagas' disease. Other inhibitors of this type, such as SCH 56592, have also shown curative, rather than suppressive, activity against T. cruzi in these models. Leishmania species have different susceptibilities to sterol biosynthesis inhibitors, both in vitro and in vivo. Leishmania braziliensis promastigotes, naturally resistant to C14α-demethylase inhibitors such as ketoconazole and D0870, were susceptible to these drugs when used in combination with the squalene epoxidase inhibitor terbinafine. Inhibitors of Δ24(25) sterol methyl transferase have been shown to act as potent antiproliferative agents against Trypanosoma cruzi, both in vitro and in vivo. New inhibitors of this type which show enhanced activity and novel mechanisms of action have been synthesized. Recent work has also demonstrated that this type of enzyme inhibitors can block sterol biosynthesis and cell proliferation in Pneumocystis carinii, a fungal pathogen which had previously been found resistant to other sterol biosynthesis inhibitors. Ajoene, an antiplatelet compound derived from garlic, was shown to have potent antiproliferative activity against epimastigotes and amastigotes of Trypanosoma cruzi in vitro; this activity was associated with a significant alteration of the phospholipid composition of the cells with no significant effects on the sterol content. In addition, alkyllsophospholipids such as ilmofosine, miltefosine and edelfosine have been shown to block the proliferation of T. cruzi and Leishmania and alter both the phospholipid and sterol composition. These results indicate the potential of lipid biosynthesis inhibitors as useful therapeutic agents in the treatment of leishmaniasis and Chagas' disease.

scholarly journals Chemical Mechanism of UDP-Galactopyranose Mutase from Trypanosoma cruzi: A Potential Drug Target against Chagas' Disease

PLoS ONE ◽  
2012 ◽  
Vol 7 (3) ◽  
pp. e32918 ◽  
Author(s):  
Michelle Oppenheimer ◽  
Ana Lisa Valenciano ◽  
Karina Kizjakina ◽  
Jun Qi ◽  
Pablo Sobrado
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Drug Target ◽  
Chemical Mechanism ◽  
Potential Drug Target ◽  
Potential Drug

scholarly journals Tolerance of Benznidazole in Treatment of Chagas' Disease in Adults

2010 ◽  
Vol 54 (11) ◽  
pp. 4896-4899 ◽  
Author(s):  
María-Jesús Pinazo ◽  
José Muñoz ◽  
Elizabeth Posada ◽  
Paulo López-Chejade ◽  
Montserrat Gállego ◽  
...  
Keyword(s):  
Public Health ◽  
Side Effects ◽  
Trypanosoma Cruzi ◽  
European Country ◽  
Chagas Disease ◽  
Health Problem ◽  
Public Health Problem ◽  
Acute Stage ◽  
Chronic Stage

ABSTRACT Chagas’ disease is an emerging public health problem in areas where the disease is not endemic. Treatment with benznidazole has shown efficacy in the acute stage of the disease, but its efficacy in the chronic stage remains controversial, and unwanted side effects are more frequent and severe in adults than in children. This study describes the profile of side effects of benznidazole in a cohort of Trypanosoma cruzi-infected patients in a European country.

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