Molecular design aided by random forests and synthesis of potent trypanocidal agents as cruzain inhibitors for Chagas disease treatment

2020 ◽  
Vol 96 (3) ◽  
pp. 948-960
Author(s):  
Sérgio Albuquerque ◽  
Lorenzo Cianni ◽  
Daniela Vita ◽  
Carla Duque ◽  
Ana S. M. Gomes ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Random Forests ◽  
Molecular Design ◽  
Disease Treatment ◽  
Cruzain Inhibitors

scholarly journals Tetradentate polyamines as efficient metallodrugs for Chagas disease treatment in murine model

2016 ◽  
Vol 29 (2) ◽  
pp. 83-93 ◽  
Author(s):  
Francisco Olmo ◽  
Miquel Costas ◽  
Clotilde Marín ◽  
Maria José Rosales ◽  
Rubén Martín-Escolano ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Murine Model ◽  
Disease Treatment

scholarly journals Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors

2015 ◽  
Vol 9 (7) ◽  
pp. e0003916 ◽  
Author(s):  
Leandro A. A. Avelar ◽  
Cristian D. Camilo ◽  
Sérgio de Albuquerque ◽  
William B. Fernandes ◽  
Cristiana Gonçalez ◽  
...  
Keyword(s):  
Molecular Design ◽  
Design Synthesis ◽  
Trypanocidal Activity ◽  
Cruzain Inhibitors

scholarly journals Looking for combination of benznidazole and Trypanosoma cruzi-triosephosphate isomerase inhibitors for Chagas disease treatment

2018 ◽  
Vol 113 (3) ◽  
pp. 153-160 ◽  
Author(s):  
Elena Aguilera ◽  
Javier Varela ◽  
Elva Serna ◽  
Susana Torres ◽  
Gloria Yaluff ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Triosephosphate Isomerase ◽  
Disease Treatment

scholarly journals T-Cell Immunophenotyping and Cytokine Production Analysis in Patients with Chagas Disease 4 Years after Benznidazole Treatment

2019 ◽  
Vol 87 (8) ◽  
Author(s):  
Mauricio Llaguno ◽  
Marcos Vinicius da Silva ◽  
Lara Rocha Batista ◽  
Djalma Alexandre Alves da Silva ◽  
Rodrigo Cunha de Sousa ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Chronic Phase ◽  
Interleukin 10 ◽  
T Helper ◽  
T Helper 1 ◽  
Cardiac Damage ◽  
Disease Treatment ◽  
Indeterminate Form ◽  
Ifn Γ

ABSTRACT The major problem with Chagas disease is evolution of the chronic indeterminate form to a progressive cardiac disease. Treatment diminishes parasitemia but not clinical progression, and the immunological features involved are unclear. Here, we studied the clinical course and the immune response in patients with chronic-phase Chagas disease at 48 months after benznidazole treatment. Progression to the cardiac form of Chagas disease or its aggravation was associated with higher in vitro antigen-specific production of interferon gamma (IFN-γ) in patients with cardiac Chagas disease than in patients with the indeterminate form. Predominance of IFN-γ production over interleukin-10 (IL-10) production in antigen-specific cultures was associated with cardiac involvement. Significantly higher numbers of antigen-specific T helper 1 cells (T-Bet+ IFN-γ+) and a significantly higher IFN-γ+/IL-10+ ratio were observed in patients with cardiac Chagas disease than in patients with the indeterminate form. Cardiac damage was associated with higher numbers of T helper cells than cytotoxic T lymphocytes producing IFN-γ. Patients with cardiac Chagas disease had predominant CD25− and CD25low T regulatory (Treg) subpopulations, whereas patients with the indeterminate form manifested a higher relative mean percentage of CD25high Treg subpopulations. These findings suggest that at 48 months after benznidazole treatment, the disease can worsen or progress to the cardiac form. The progression may be related to increased IFN-γ production (mostly from CD4+ T cells) relative to IL-10 production and increased Treg percentages. Patients with the indeterminate form of Chagas disease show a more balanced ratio of proinflammatory and anti-inflammatory cytokines.

Perspectives in Chagas Disease Treatment

Global Heart ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. 189 ◽  
Author(s):  
Gustavo Bernardes F. Oliveira ◽  
Álvaro Avezum ◽  
Antônio José Cordeiro Mattos
Keyword(s):  
Chagas Disease ◽  
Disease Treatment

scholarly journals Improved Completion Rates and Characterization of Drug Reactions with an Intensive Chagas Disease Treatment Program in Rural Bolivia

2013 ◽  
Vol 7 (9) ◽  
pp. e2407 ◽  
Author(s):  
Jeffrey A. Tornheim ◽  
Daniel F. Lozano Beltran ◽  
Robert H. Gilman ◽  
Mario Castellon ◽  
Marco A. Solano Mercado ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Treatment Program ◽  
Completion Rates ◽  
Drug Reactions ◽  
Disease Treatment

scholarly journals Chagas Disease Treatment and Rational Drug Discovery: A Challenge That Remains

2019 ◽  
Vol 10 ◽  
Author(s):  
Ana Catarina Cristovão Silva ◽  
Maria Carolina Accioly Brelaz-de-Castro ◽  
Ana Cristina Lima Leite ◽  
Valéria Rêgo Alves Pereira ◽  
Marcelo Zaldini Hernandes
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Disease Treatment ◽  
Rational Drug

scholarly journals Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy

2010 ◽  
Vol 53 (4) ◽  
pp. 1763-1773 ◽  
Author(s):  
Katrien Brak ◽  
Iain D. Kerr ◽  
Kimberly T. Barrett ◽  
Nobuhiro Fuchi ◽  
Moumita Debnath ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Cruzain Inhibitors

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.

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