Identification of Levothyroxine Antichagasic Activity through Computer-Aided Drug Repurposing

Bellera, Carolina L.; Balcazar, Darío Emmanuel; Alberca, Lucas Nicolás; Labriola, Carlos; Talevi, Alan; Carrillo, Carolina

doi:10.1155/2014/279618

Cited by 21 publications

(15 citation statements)

References 43 publications

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“…Other compounds have been identified by drug repositioning as possible trypanocidal drugs using different targets; such as the cruzipain [61][62][63][64], some T. cruzi kinases [65][66][67] and the trans-sialidase [68], among other examples. Other drug repurposing approaches have inferred the possible trypanocidal activity of already-approved drugs based on the reported effect or mechanism of action of some compounds in other organisms [69][70][71][72][73][74].…”

Section: Discussionmentioning

confidence: 99%

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

et al. 2020

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Background Crystal violet (CV) was used for several years in blood banks to eliminate the parasite Trypanosoma cruzi in endemic areas in order to prevent transfusion-transmitted Chagas disease. One mechanism of action described for CV involves inhibition of proline uptake. In T. cruzi, proline is essential for host cell infection and intracellular differentiation among other processes, and can be obtained through the proline permease TcAAAP069. Methodology/Principal findings CV inhibited proline transporter TcAAAP069 and parasites overexpressing this permease were 47-fold more sensitive to this compound than control parasites. Using CV as reference molecule, loratadine, cyproheptadine, olanzapine and clofazimine were identified as structurally related compounds to CV (structural analogues) by in silico drug repurposing through a similarity-based virtual screening protocol. All these already-approved drugs for clinical use inhibited TcAAAP069 activity with different efficacies and also presented trypanocidal action in epimastigotes, trypomastigotes and amastigotes of the Y, CL Brener and Dm28c T. cruzi strains. Finally, a synergistic effect between benznidazole and the CV chemical analogues was evidenced by combination and dose-reduction indexes values in epimastigotes and trypomastigotes of the Y strain. Conclusions/Significance Loratadine, cyproheptadine and clofazimine inhibit TcAAAP069 proline transporter and also present trypanocidal effect against all T. cruzi life stages in strains from three different DTUs. These CV structural analogues could be a starting point to design therapeutic alternatives to treat Chagas disease by finding new indications for old drugs. This approach,

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Section: Discussionmentioning

confidence: 99%

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

et al. 2020

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“…Untreated controls were performed under the same culture conditions with equal concentrations of DMSO as for candidate drugs. After 3 and 7 d, the number of viable parasites was counted using a haemocytometer chamber under light microscope and results were expressed as percentage respect of the untreated controls 73 .…”

Section: Biological Assaysmentioning

confidence: 99%

A structure-based approach towards the identification of novel antichagasic compounds: Trypanosoma cruzi carbonic anhydrase inhibitors

Llanos

Sbaraglini

Villalba

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Trypanosoma cruzi carbonic anhydrase (TcCA) has recently emerged as an interesting target for the design of new compounds to treat Chagas disease. In this study we report the results of a structure-based virtual screening campaign to identify novel and selective TcCA inhibitors. The combination of properly validated computational methodologies such as comparative modelling, molecular dynamics and docking simulations allowed us to find high potency hits, with KI values in the nanomolar range. The compounds also showed trypanocidal effects against T. cruzi epimastigotes and trypomastigotes. All the candidates are selective for inhibiting TcCA over the human isoform CA II, which is encouraging in terms of possible therapeutic safety and efficacy.

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“…Development of cruzipain inhibitors by structure activity relationship (SAR) studies, combinatorial chemistry, HTS, and virtual screening are also employed in repositioning strategies [128]. Bromocriptine (antiparkinson and antidiabetic drug), amiodarone (antiarrhythmic drug), and levothyroxine (hypothyroidism drug) were selected in a screening campaign for cruzain inhibitors of the DrugBank database [129], clofazimine (antileprosy drug) and benidipine (antihypertensive) from the Merck Index 12th database [130,131], and etofyllin clofibrate (antilipemic drug) and piperacillin, cefoperazone, and flucloxacillin (β-lactam antibiotics) from a collection of 3180 FDA drugs [132].…”

Section: Cysteine Proteasesmentioning

confidence: 99%

Parasite, Compartments, and Molecules: Trick versus Treatment on Chagas Disease

Vannier‐Santos¹,

Brunoro²,

Soeiro³

et al. 2019

Biology OfTrypanosoma Cruzi

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Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic to Latin America, standing out as a socioeconomic problem for low-income tropical populations. Such disease affects millions of people worldwide and emerges in nonendemic areas due to migration and climate changes. The current chemotherapy is restricted to two nitroderivatives (benznidazole and nifurtimox), which is unsatisfactory due to limited efficacy (particularly in chronic phase) and adverse side effects. T. cruzi life cycle is complex, including invertebrate and vertebrate hosts and three developmental forms (epimastigotes, trypomastigotes, and amastigotes). In this chapter, we will discuss promising cellular and molecular targets present in the vertebrate-dwelling forms of the parasite (trypomastigotes and amastigotes). Among the cellular targets, the mitochondrion is the most frequently studied; while among the molecular ones, we highlight squalene synthase, C14α-sterol demethylase, and cysteine proteases. In this scenario, proteomics becomes a valuable tool for the identification of other molecular targets, and some previously identified candidates will be also discussed. Multidisciplinary studies are needed to identify novel key molecules in T. cruzi in order to increase trypanocidal activity and reduce mammalian toxicity, ensuring the development of novel drugs for Chagas disease.

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Identification of Levothyroxine Antichagasic Activity through Computer-Aided Drug Repurposing

Cited by 21 publications

References 43 publications

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

A structure-based approach towards the identification of novel antichagasic compounds: Trypanosoma cruzi carbonic anhydrase inhibitors

Parasite, Compartments, and Molecules: Trick versus Treatment on Chagas Disease

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