scholarly journals Trypanosoma cruzi Presenilin-Like Transmembrane Aspartyl Protease: Characterization and Cellular Localization

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1564
Author(s):  
Guilherme C. Lechuga ◽  
Paloma Napoleão-Pêgo ◽  
Carolina C. G. Bottino ◽  
Rosa T. Pinho ◽  
David W. Provance-Jr ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Cellular Localization ◽  
Secretory Pathway ◽  
Chronic Phase ◽  
Basic Research ◽  
New Drugs ◽  
Public Health Issue ◽  
Spot Synthesis ◽  
Major Public Health Issue ◽  
Computational Analyses

The increasing detection of infections of Trypanosoma cruzi, the etiological agent of Chagas disease, in non-endemic regions beyond Latin America has risen to be a major public health issue. With an impact in the millions of people, current treatments rely on antiquated drugs that produce severe side effects and are considered nearly ineffective for the chronic phase. The minimal progress in the development of new drugs highlights the need for advances in basic research on crucial biochemical pathways in T. cruzi to identify new targets. Here, we report on the T. cruzi presenilin-like transmembrane aspartyl enzyme, a protease of the aspartic class in a unique phylogenetic subgroup with T. vivax separate from protozoans. Computational analyses suggest it contains nine transmembrane domains and an active site with the characteristic PALP motif of the A22 family. Multiple linear B-cell epitopes were identified by SPOT-synthesis analysis with Chagasic patient sera. Two were chosen to generate rabbit antisera, whose signal was primarily localized to the flagellar pocket, intracellular vesicles, and endoplasmic reticulum in parasites by whole-cell immunofluorescence. The results suggest that the parasitic presenilin-like enzyme could have a role in the secretory pathway and serve as a target for the generation of new therapeutics specific to the T. cruzi.

scholarly journals Trypanosoma Cruzi Presenilin-like Transmembrane Aspartyl Protease: Characterization and Cellular Localization

2020 ◽  
Author(s):  
Guilherme C. Lechuga ◽  
Paloma Napoleão-Pêgo ◽  
Carolina C.G. Bottino ◽  
Rosa T. Pinho ◽  
David W. Provance-Jr ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Cellular Localization ◽  
Secretory Pathway ◽  
Chronic Phase ◽  
Basic Research ◽  
New Drugs ◽  
Public Health Issue ◽  
Spot Synthesis ◽  
Major Public Health Issue ◽  
Computational Analyses

The increasing detection of infections of Trypanosoma cruzi, the etiological agent of Chagas disease, in non-endemic regions beyond Latin America has risen to be a major public health issue. With an impact in the millions of people, current treatments rely on antiquated drugs that produce severe side effects and are considered nearly ineffective for the chronic phase. The minimal progress in the development of new drugs highlights the need for advances in basic research on crucial biochemical pathways in T. cruzi to identify new targets. Here, we report on the T. cruzi presenilin-like transmembrane aspartyl enzyme, a protease of the aspartic class in a unique phylogenetic subgroup with T. vivax separate from protozoans. Computational analyses suggests it contains 9 transmembrane domains and an active site with the characteristic PALP motif of the A22 family. Multiple linear B-cell epitopes were identified by SPOT synthesis analysis with Chagasic patient sera. Two were chosen to generate rabbit antisera, whose signal was primarily localized to the flagellar pocket, intracellular vesicles and endoplasmic reticulum in parasites by whole cell immunofluorescence. The results suggest that the parasitic presenilin-like enzyme could have a role in the secretory pathway and serve as a biomarker for infections.

scholarly journals Capsaicin inhibits arginine kinase and exerts anti-Trypanosoma cruzi activity

2020 ◽  
Author(s):  
Edward A. Valera-Vera ◽  
Chantal Reigada ◽  
Melisa Sayé ◽  
Fabio A. Digirolamo ◽  
Mariana R. Miranda ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Stress Responses ◽  
Mammalian Cells ◽  
Arginine Kinase ◽  
Chronic Phase ◽  
New Drugs ◽  
World Health ◽  
Neglected Diseases ◽  
Health Organization

ABSTRACTTrypanosoma cruzi is the causative agent of Chagas disease, considered within the list of twenty neglected diseases according to the World Health Organization. There are only two therapeutic drugs for Chagas disease, both of them unsuitable for the chronic phase, therefore the development of new drugs is a priority.T. cruzi arginine kinase (TcAK) is a promising drug target since it is absent in humans and it is involved in cellular stress responses. In a previous study from our laboratory, possible TcAK inhibitors were identified through computer simulations, resulting in the best-scoring compounds cyanidin derivatives and capsaicin. Considering these results, in this work we evaluate the effect of capsaicin on TcAK activity and its trypanocidal effect. Although capsaicin produced a weak inhibition on the recombinant TcAK activity (IC50 ≈ 800 µM), it had a strong trypanocidal effect on epimastigotes and trypomastigotes (IC50 = 6.26 µM and 0.26 µM, respectively) being 20-fold more active on trypomastigotes than mammalian cells. Epimastigotes that overexpress TcAK were 37% more resistant to capsaicin than wild type parasites, suggesting that trypanocidal activity could be due, in part, to the enzyme inhibition. However, the difference between the concentrations at which the enzyme is inhibited and the parasite death is caused implies the presence of other targets. In this sense, the prohibitin-2 and calmodulin were identified as other possible capsaicin targets. Capsaicin is a strong and selective trypanocidal agent active in nanomolar concentrations, with an IC50 57-fold lower than benznidazole, the drug currently used for treating Chagas disease.

New Trypanosoma cruzi Trypanothione Reductase Inhibitors Identification using the Virtual Screening in Database of Nucleus Bioassay, Biosynthesis and Ecophysiology (NuBBE)

2019 ◽  
Vol 17 (2) ◽  
pp. 138-149
Author(s):  
Nelcí do Carmo Santos ◽  
Vinícius G. da Paixão ◽  
Samuel S. da Rocha Pita
Keyword(s):  
Virtual Screening ◽  
Trypanosoma Cruzi ◽  
Chronic Phase ◽  
Conclusive Evidence ◽  
New Drugs ◽  
Trypanothione Reductase ◽  
Efficacy And Safety ◽  
Reductase Inhibitors ◽  
Preclinical Trials

Background: American trypanosomiasis, also known as Chagas disease, is caused by the protozoan Trypanosoma cruzi (T. cruzi) and affects approximately 10 to 12 million, primarily in Latin America. Since its discovery in 1909, there is no effective treatment for its chronic phase, with benzonidazole being the only anti-trypanosoma drug used in Brazil, despite the absence of conclusive evidence to prove its efficacy and safety. Thus, it is necessary to develop new drugs that are more effective and selective against Trypanosoma cruzi. Methods: The T. cruzi enzyme Trypanothione Reductase (TcTR) is a validated target for the discovery of new antiprotozoal compounds and we employed the Virtual Screening technique on the database of Nucleus of Bioassays, Biosynthesis and Ecophysiology (NuBBE), aiming to search for new chemical moieties against T. cruzi. From these we selected the 10 best ligand energies interactions and verified their interaction profile with the main TcTR sites through the AuPosSOM server (https://www.biomedicale.univ-paris5.fr/aupossom). Results and Conclusion: Finally, we analyzed some pharmacokinetics and toxicological information through the servers Aggregator Advisor (http://advisor.bkslab.org), Pred-hERG 4.0 (http://labmol.com.br/predherg) and pkCSM (http://biosig.unimelb.edu.au/pkcsm/prediction) which we expect will be useful in in vitro preclinical trials.</P>

scholarly journals Detection of parasite-derived transrenal DNA for the diagnosis of chronic Trypanosoma cruzi infection

2019 ◽  
Author(s):  
Ana G. Madrigal ◽  
Rachel Marcus ◽  
Robert Gilman ◽  
Alan L. Scott ◽  
Clive Shiff
Keyword(s):  
Trypanosoma Cruzi ◽  
Chronic Phase ◽  
Protozoan Parasite ◽  
Public Health Issue ◽  
Global Public Health ◽  
Detection Approach ◽  
Life Threatening ◽  
No Gold Standard ◽  
Antibody Tests ◽  
Cruzi Infection

AbstractChagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a potentially life-threatening infection endemic to Latin America that has emerged as a global public health issue due to globalization and emigration patterns. Diagnosis of T. cruzi infection is complex, especially for the chronic phase of the disease that is characterized by a low to moderate burden of the difficult to detect, tissue-dwelling, intracellular form of the parasite. Diagnosis relies on a multistep indirect serological detection approach that requires positive results in at least two independent anti-T. cruzi antibody tests. With no gold standard diagnostic method for chronic T. cruzi, new approaches are needed that can more directly test for the presence of the parasite. Here, we report on of the potential utility of a noninvasive diagnostic approach that specifically detects T. cruzi-derived cell-free repeat DNA in the urine of patients who are both serologically positive and negative.

Effect of capsaicin on the protozoan parasite Trypanosoma cruzi

2020 ◽  
Vol 367 (23) ◽  
Author(s):  
Edward A Valera-Vera ◽  
Chantal Reigada ◽  
Melisa Sayé ◽  
Fabio A Digirolamo ◽  
Facundo Galceran ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Stress Responses ◽  
Mammalian Cells ◽  
Arginine Kinase ◽  
Chronic Phase ◽  
Protozoan Parasite ◽  
New Drugs ◽  
Cellular Stress Responses ◽  
The Difference

ABSTRACT Trypanosoma cruzi is the causative agent of Chagas disease. There are only two approved treatments, both of them unsuitable for the chronic phase, therefore the development of new drugs is a priority. Trypanosoma cruzi arginine kinase (TcAK) is a promising drug target since it is absent in humans and it is involved in cellular stress responses. In a previous study, possible TcAK inhibitors were identified through computer simulations resulting the best compounds capsaicin and cyanidin derivatives. Here, we evaluate the effect of capsaicin on TcAK activity and its trypanocidal effect. Although capsaicin produced a weak enzyme inhibition, it had a strong trypanocidal effect on epimastigotes and trypomastigotes (IC50 = 6.26 µM and 0.26 µM, respectively) being 20-fold more active on trypomastigotes than mammalian cells. Capsaicin was also active on the intracellular cycle reducing by half the burst of trypomastigotes at approximately 2 µM. Considering the difference between the concentrations at which parasite death and TcAK inhibition occur, other possible targets were predicted. Capsaicin is a selective trypanocidal agent active in nanomolar concentrations, with an IC50 57-fold lower than benznidazole, the drug currently used for treating Chagas disease.

Repurposing strategies for Chagas disease therapy: the effect of imatinib and derivatives against Trypanosoma cruzi

Parasitology ◽  
2019 ◽  
Vol 146 (8) ◽  
pp. 1006-1012 ◽  
Author(s):  
M. R. Simões-Silva ◽  
J. S. De Araújo ◽  
R. B. Peres ◽  
P. B. Da Silva ◽  
M. M. Batista ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Kinase Inhibitor ◽  
Fixed Ratio ◽  
Chronic Phase ◽  
Host Cells ◽  
Public Health Issue ◽  
Mammalian Host ◽  
Neglected Diseases

AbstractChagas disease (CD) is a neglected parasitic condition endemic in the Americas caused by Trypanosoma cruzi. Patients present an acute phase that may or not be symptomatic, followed by lifelong chronic stage, mostly indeterminate, or with cardiac and/or digestive progressive lesions. Benznidazole (BZ) and nifurtimox are the only drugs approved for treatment but not effective in the late chronic phase and many strains of the parasite are naturally resistant. New alternative therapy is required to address this serious public health issue. Repositioning and combination represent faster, and cheaper trial strategies encouraged for neglected diseases. The effect of imatinib (IMB), a tyrosine kinase inhibitor designed for use in neoplasias, was assessed in vitro on T. cruzi and mammalian host cells. In comparison with BZ, IMB was moderately active against different strains and forms of the parasite. The combination IMB + BZ in fixed-ratio proportions was additive. Novel 14 derivatives of IMB were screened and a 3,2-difluoro-2-phenylacetamide (3e) was as potent as BZ on T. cruzi but had low selectivity index. The results demonstrate the importance of phenotypic assays, encourage the improvement of IMB derivatives to reach selectivity and testify to the use of repurposing and combination in drug screening for CD.

scholarly journals Gonorrhea: Antimicrobial Resistance and New Drugs

2019 ◽  
Vol 77 (3) ◽  
pp. 233-238 ◽  
Author(s):  
Catarina Soares Queirós ◽  
João Borges da Costa
Keyword(s):  
Antimicrobial Resistance ◽  
Sexually Transmitted Infections ◽  
Prevention And Control ◽  
New Drugs ◽  
Public Health Issue ◽  
Global Burden ◽  
Transmitted Infection ◽  
Major Public Health Issue ◽  
Sexually Transmitted ◽  
And Control

The global burden of sexually transmitted infections remains high, with significant associated morbidity and mortality. Gonorrhea is the second most notified sexually transmitted infection in Europe, and its incidence has been increasing in the last years. Although traditionally considered a treatable infection, antimicrobial resistance of Neisseria gonorrhoeaeincludes at present also macrolides, tetracyclines, sulfonamides and trimethoprim combinations, quinolones, and even cephalosporins. These high levels of gonococcal resistance to antimicrobials resulting in untreatable infections in the future may become one of the greatest challenges to the prevention and control of sexually transmitted infections, which may be a significant major public health issue. Therefore, the development of novel antimicrobials and/or new dual antimicrobial therapy regimens is urgently needed. In this paper, evolution of antimicrobial resistance of Neisseria gonorrhoeae is reviewed, along with new drugs currently under development for the treatment of this infection.

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.

Antimicrobial peptides for the treatment of pulmonary tuberculosis, allies or foes?

2018 ◽  
Vol 24 (10) ◽  
pp. 1138-1147
Author(s):  
Bruno Rivas-Santiago ◽  
Flor Torres-Juarez
Keyword(s):  
Pulmonary Tuberculosis ◽  
Antimicrobial Peptides ◽  
Experimental Models ◽  
New Drugs ◽  
World Health ◽  
Public Health Issue ◽  
Health Organization ◽  
Drug Resistant Strains

Tuberculosis is an ancient disease that has become a serious public health issue in recent years, although increasing incidence has been controlled, deaths caused by Mycobacterium tuberculosis have been accentuated due to the emerging of multi-drug resistant strains and the comorbidity with diabetes mellitus and HIV. This situation is threatening the goals of World Health Organization (WHO) to eradicate tuberculosis in 2035. WHO has called for the creation of new drugs as an alternative for the treatment of pulmonary tuberculosis, among the plausible molecules that can be used are the Antimicrobial Peptides (AMPs). These peptides have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models, nevertheless, these peptides not only have antimicrobial activity but also have a wide variety of functions such as angiogenesis, wound healing, immunomodulation and other well-described roles into the human physiology. Therapeutic strategies for tuberculosis using AMPs must be well thought prior to their clinical use; evaluating comorbidities, family history and risk factors to other diseases, since the wide function of AMPs, they could lead to collateral undesirable effects.

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