Examination of multiple Trypanosoma cruzi targets in a new drug discovery approach for Chagas disease

Beltran-Hortelano, Iván; Alcolea, Verónica; Font, Marı́a; Pérez‐Silanes, Silvia

doi:10.1016/j.bmc.2021.116577

Cited by 35 publications

(35 citation statements)

References 196 publications

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“…TR is one of the most important enzymes for the survival of parasites because it participates in redox metabolism, catalysing the reduction of trypanothione disulphide (TS 2 ) to trypanothione (TSH) [22,33,34]. Furthermore, it is considered an attractive target for the search of new anti-Chagasic agents since this enzyme is absent in mammals [33,34]. Additionally, previous studies have shown that naphthoquinones are potential TR inhibitors [21].…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

New Amino Naphthoquinone Derivatives as Anti-Trypanosoma cruzi Agents Targeting Trypanothione Reductase

et al. 2022

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To develop novel chemotherapeutic alternatives for the treatment of Chagas disease, in this study, a set of new amino naphthoquinone derivatives were synthesised and evaluated in vitro on the epimastigote and trypomastigote forms of Trypanosoma cruzi strains (NINOA and INC-5) and on J774 murine macrophages. The design of the new naphthoquinone derivatives considered the incorporation of nitrogenous fragments with different substitution patterns present in compounds with activity on T. cruzi, and, thus, 19 compounds were synthesised in a simple manner. Compounds 2e and 7j showed the lowest IC50 values (0.43 µM against both strains for 2e and 0.19 µM and 0.92 µM for 7j). Likewise, 7j was more potent than the reference drug, benznidazole, and was more selective on epimastigotes. To postulate a possible mechanism of action, molecular docking studies were performed on T. cruzi trypanothione reductase (TcTR), specifically at a site in the dimer interface, which is a binding site for this type of naphthoquinone. Interestingly, 7j was one of the compounds that showed the best interaction profile on the enzyme; therefore, 7j was evaluated on TR, which behaved as a non-competitive inhibitor. Finally, 7j was predicted to have a good pharmacokinetic profile for oral administration. Thus, the naphthoquinone nucleus should be considered in the search for new trypanocidal agents based on our hit 7j.

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Section: Molecular Docking Studiesmentioning

confidence: 99%

New Amino Naphthoquinone Derivatives as Anti-Trypanosoma cruzi Agents Targeting Trypanothione Reductase

et al. 2022

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“…The active site, which is composed of three conserved key residues, Lys13, His95, and Glu165, has been explored as a possible target for cancer therapy [95]. In addition to the active site, the nonconserved dimerization site of the parasitic TPI has been targeted by small-molecule inhibitors [96]. Both the active and dimerization sites in the human TPI could, therefore, be potentially targeted to develop SCD therapeutics.…”

Section: Glyceraldehyde-3-phosphate Dehydrogenase (Gapdh)mentioning

confidence: 99%

Metabolic Reprogramming in Sickle Cell Diseases: Pathophysiology and Drug Discovery Opportunities

Alramadhani

Aljahdali

Abdulmalik

et al. 2022

IJMS

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Sickle cell disease (SCD) is a genetic disorder that affects millions of individuals worldwide. Chronic anemia, hemolysis, and vasculopathy are associated with SCD, and their role has been well characterized. These symptoms stem from hemoglobin (Hb) polymerization, which is the primary event in the molecular pathogenesis of SCD and contributes to erythrocyte or red blood cell (RBC) sickling, stiffness, and vaso-occlusion. The disease is caused by a mutation at the sixth position of the β-globin gene, coding for sickle Hb (HbS) instead of normal adult Hb (HbA), which under hypoxic conditions polymerizes into rigid fibers to distort the shapes of the RBCs. Only a few therapies are available, with the universal effectiveness of recently approved therapies still being monitored. In this review, we first focus on how sickle RBCs have altered metabolism and then highlight how this understanding reveals potential targets involved in the pathogenesis of the disease, which can be leveraged to create novel therapeutics for SCD.

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“…Moreover, frequent adverse effects and long administration regimens hinder their acceptability and patients adherence to treatment (Jackson et al, 2010;Aldasoro et al, 2018;Peŕez-Molina and Molina, 2018). Thus, the development of new drugs, particularly for the chronic stage of the infection, is urgently needed (Beltran-Hortelano et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Identification of compounds with activity against Trypanosoma cruzi within a collection of synthetic nucleoside analogs

Barnadas-Carceller

Martínez-Peinado

Gómez

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionChagas disease is caused by the protozoan parasite Trypanosoma cruzi, and it is the most important neglected tropical disease in the Americas. Two drugs are available to treat the infection, but their efficacy in the chronic stage of the disease, when most cases are diagnosed, is reduced. Their tolerability is also hindered by common adverse effects, making the development of safer and efficacious alternatives a pressing need. T. cruzi is unable to synthesize purines de novo, relying on a purine salvage pathway to acquire these from its host, making it an attractive target for the development of new drugs. MethodsWe evaluated the anti-parasitic activity of 23 purine analogs with different substitutions in the complementary chains of their purine rings. We sequentially screened the compounds' capacity to inhibit parasite growth, their toxicity in Vero and HepG2 cells, and their specific capacity to inhibit the development of amastigotes. We then used in-silico docking to identify their likely targets.ResultsEight compounds showed specific anti-parasitic activity, with IC50 values ranging from 2.42 to 8.16 μM. Adenine phosphoribosyl transferase, and hypoxanthine-guanine phosphoribosyl transferase, are their most likely targets. DiscussionOur results illustrate the potential role of the purine salvage pathway as a target route for the development of alternative treatments against T. cruzi infection, highlithing the apparent importance of specific substitutions, like the presence of benzene groups in the C8 position of the purine ring, consistently associated with a high and specific anti-parasitic activity.

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Examination of multiple Trypanosoma cruzi targets in a new drug discovery approach for Chagas disease

Cited by 35 publications

References 196 publications

New Amino Naphthoquinone Derivatives as Anti-Trypanosoma cruzi Agents Targeting Trypanothione Reductase

New Amino Naphthoquinone Derivatives as Anti-Trypanosoma cruzi Agents Targeting Trypanothione Reductase

Metabolic Reprogramming in Sickle Cell Diseases: Pathophysiology and Drug Discovery Opportunities

Identification of compounds with activity against Trypanosoma cruzi within a collection of synthetic nucleoside analogs

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