Silent Information Regulator 2 from Trypanosoma cruzi Is a Potential Target to Infection Control (original) (raw)
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Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease
PLoS neglected tropical diseases, 2018
Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnap...
Pharmaceuticals
Trypanosoma cruzi, the etiological agent of Chagas disease, relies on finely coordinated epigenetic regulation during the transition between hosts. Herein we targeted the silent information regulator 2 (Sir2) enzyme, a NAD+-dependent class III histone deacetylase, to interfere with the parasites’ cell cycle. A combination of molecular modelling with on-target experimental validation was used to discover new inhibitors from commercially available compound libraries. We selected six inhibitors from the virtual screening, which were validated on the recombinant Sir2 enzyme. The most potent inhibitor (CDMS-01, IC50 = 40 μM) was chosen as a potential lead compound.
Characterization of Trypanosoma cruzi sirtuins as possible drug targets for Chagas Disease
Antimicrobial Agents and Chemotherapy, 2015
Acetylation of lysine is a major posttranslational modification of proteins and is catalyzed by lysine acetyltransferases, while lysine deacetylases remove acetyl groups. Among the deacetylases, the sirtuins are NAD+-dependent enzymes, which modulate gene silencing, DNA damage repair, and several metabolic processes. As sirtuin-specific inhibitors have been proposed as drugs for inhibiting the proliferation of tumor cells, in this study, we investigated the role of these inhibitors in the growth and differentiation ofTrypanosoma cruzi, the agent of Chagas disease. We found that the use of salermide during parasite infection prevented growth and initial multiplication after mammalian cell invasion byT. cruziat concentrations that did not affect host cell viability. In addition,in vivoinfection was partially controlled upon administration of salermide. There are two sirtuins inT. cruzi, TcSir2rp1 and TcSir2rp3. By using specific antibodies and cell lines overexpressing the tagged vers...
International Journal of Molecular Sciences, 2020
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 prolife...
Parasitology, 2014
Chagas disease, which is caused by the parasite Trypanosoma cruzi, affects approximately 7-8 million people in Latin America. The drugs available to treat this disease are ineffective against chronic phase disease and are associated with toxic side effects. Therefore, the development of new compounds that can kill T. cruzi at low concentrations is critically important. Herein, we report the effects of a novel 3-arylideneindolin-2-one that inhibits sirtuins, which are highly conserved proteins that are involved in a variety of physiological processes. The compound KH-TFMDI was tested against the epimastigote, trypomastigote and amastigote forms of T. cruzi, and its effects were evaluated using flow cytometry, light and electron microscopy. KH-TFMDI inhibited the replication of T. cruzi intracellular amastigotes with an IC 50 of 0·5 ± 0·2 μM, which is significantly lower than the IC 50 of benznidazole. The compound also lysed the highly infectious bloodstream trypomastigotes (BST) with LC 50 values of 0·8 ± 0·3 μM at 4°C and 2·5 ± 1·1 μM at 37°C. KH-TFMDI inhibited cytokinesis and induced several morphological changes in the parasite, leading to its death by apoptosis and autophagy. This study highlights sirtuins as a potential new target for Chagas disease therapy.
New Therapeutic Targets for Drug Design Against Trypanosoma cruzi, Advances and Perspectives
Current Medicinal Chemistry, 2009
Chagas disease is one of the most important parasitic diseases in Latin America, affecting16 to 18 million people. Nifurtimox and Benznidazol are drugs that are commonly used in its treatment; however, these drugs produce several adverse reactions and are not effective in the chronic phase of the disease. Therefore, the design, synthesis, and biological evaluation of new compounds with potential activity against Trypanozoma cruzi are of great importance. We review six proteins involved in the biochemical metabolism of Trypanosoma cruzi that have recently been studied as potential targets for designing new drugs for Chagas disease. These are farnesyl pyrophosphate synthase, trans-sialidase, cruzain cystein protease, trypanothione reductase, glucose 6-phosphate-dehydrogenase, glyceraldehyde 3-phosphatedehydrogenase, and-hydroxy acid dehydrogenase. We also review the advances of compounds recently designed based on structure-activity, and the perspectives of new compounds that inhibit these therapeutic targets.
Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Medicinal Chemistry of Neglected and Tropical Diseases, 2019
The Neglected Tropical Diseases (NTDs) are a group of 17 pathologies, recognized by the World Health Organization (WHO), which are endemic in 149 countries of tropical and sub-tropical areas of the globe, and affect more than one billion people overall (Feasey et al. 2010). The pathologies are all caused by microparasites or macroparasites. Among the diseases provoked by microparasites, three are caused by kinetoplastidae, a group of flagellated protozoa transmitted by insect vectors: Chagas disease, Human African Trypanosomiasis and leishmaniasis. The focus of the present chapter is on the identification of new drugs for the treatment of trypanosomatidic infections such as Chagas disease, caused by Trypanosoma cruzi, and Human African Trypanosomiasis, caused by Trypanosoma brucei (Filardy et al. 2018).
Identification of Small-Molecule Inhibitors of Trypansoma cruzi Infection - Probe 3
2011
which is endemic to Central and South America. Approximately 13 million people are infected with the parasite, and 25-30% of infected patients suffer from irreversible damage to the heart and digestive tract resulting in disability and death within 20 years of infection. Few treatments are available with limited effectiveness only against the early (acute) stages of disease, significant toxicity, and widespread drug resistance. We report the outcome of a high-throughput chemical library screen to identify novel, nontoxic, small-molecule inhibitors of T. cruzi, which will aid the development of more potent and selective therapies for both the acute and chronic stages of Chagas disease. Of the 303,224-screened compounds, 35 compounds were chosen based on their selectivity, potency, and chemical tractability. Of those, 27 dry powder-validated compounds were retested in the primary screen, secondary assays, and an orthogonal screen.
Disease Markers, 2020
Chagas disease is a neglected tropical disease caused by the parasite Trypanosoma cruzi. Despite the efforts and distinct methodologies, the search of antigens for diagnosis, vaccine, and drug targets for the disease is still needed. The present study is aimed at identifying possible antigens that could be used for diagnosis, vaccine, and drugs targets against T. cruzi using reverse vaccinology and molecular docking. The genomes of 28 T. cruzi strains available in GenBank (NCBI) were used to obtain the genomic core. Then, subtractive genomics was carried out to identify nonhomologous genes to the host in the core. A total of 2630 conserved proteins in 28 strains of T. cruzi were predicted using OrthoFinder and Diamond software, in which 515 showed no homology to the human host. These proteins were evaluated for their subcellular localization, from which 214 are cytoplasmic and 117 are secreted or present in the plasma membrane. To identify the antigens for diagnosis and vaccine targ...
Human African trypanosomiasis is a neglected tropical disease that is lethal if left untreated. Existing therapeutics have limited efficacy and severe associated toxicities. 2- imidazol-2-yl)amino)propyl)amino)methyl)-4,6dichloro-1H-indol-1-yl)ethan-1-ol (NEU-1053) has recently been identified from a high-throughput screen of >42,000 compounds as a highly potent and fast-acting trypanocidal agent capable of curing a bloodstream infection of Trypanosoma brucei in mice. We have designed a library of analogues to probe the structure−activity relationship and improve the predicted central nervous system (CNS) exposure of NEU-1053. We report the activity of these inhibitors of T. brucei, the efficacy of NEU-1053 in a murine CNS model of infection, and identification of the target of NEU-1053 via X-ray crystallography.