A Decade of Targets and Patented Drugs for Chemotherapy of Chagas Disease

Duschak, Vilma G.

doi:10.2174/157489111796887864

Cited by 26 publications

(26 citation statements)

References 311 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Complexes with at least two hot spots in close proximity were cross-checked for presence in existing databases of helix [23,24] and loop [25,26] interaction motifs, then with existing literature for experimentally verified interface hot spots, and finally for identity as an established or emerging drug target [27–31]. Amino acid residues falling just below the threshold (ΔΔG between 0.8 and 1.0 REU) were also considered when proximal to multiple interface hot spots.…”

Section: Methodsmentioning

confidence: 99%

Essential multimeric enzymes in kinetoplastid parasites: A host of potentially druggable protein-protein interactions

2017

View full text Add to dashboard Cite

Parasitic diseases caused by kinetoplastid parasites of the genera Trypanosoma and Leishmania are an urgent public health crisis in the developing world. These closely related species possess a number of multimeric enzymes in highly conserved pathways involved in vital functions, such as redox homeostasis and nucleotide synthesis. Computational alanine scanning of these protein-protein interfaces has revealed a host of potentially ligandable sites on several established and emerging anti-parasitic drug targets. Analysis of interfaces with multiple clustered hotspots has suggested several potentially inhibitable protein-protein interactions that may have been overlooked by previous large-scale analyses focusing solely on secondary structure. These protein-protein interactions provide a promising lead for the development of new peptide and macrocycle inhibitors of these enzymes.

show abstract

Section: Methodsmentioning

confidence: 99%

Essential multimeric enzymes in kinetoplastid parasites: A host of potentially druggable protein-protein interactions

2017

View full text Add to dashboard Cite

show abstract

“…This enzyme is involved in different cellular functions such as nutrition, penetration into the host cell, defense, and differentiation processes [51]. It has been extensively studied as a valid target for new drug development [52,53]. There are several three-dimensional structures of cruzipain with different inhibitors allowing the identification of structural regions of this enzyme that will enable the design of new agents [54,55].…”

Section: Cruzipainmentioning

confidence: 99%

“…The most potent derivative of 1,4 naphthoquinone was a quinone-coumarin hybrid [51] despite showing toxicity against rat skeletal myoblasts [94].Between nitrofurans compounds, several 5-nitrofuroic acid derivatives have been synthesized and evaluated against T. cruzi. The best compound was 5-nitro-furan-2-carboxylic acid dibenzyl amide [52], which it significantly increased the trypanocidal nifurtimox activity being TryTR your molecular target [95].…”

mentioning

confidence: 99%

New Approaches for Chagas’ Disease Chemotherapy

Liñares¹

2018

Chagas Disease - Basic Investigations and Challenges

View full text Add to dashboard Cite

The latest advances concerning drug design and chemotherapy development to combat the Chagas' disease are discussed. This chapter is based on the metabolic differences between the pathogenic parasite and mammal hosts that led to the progress in the search for novel metabolic pathways in parasites that may be essential for parasite's survival but with no counterpart in the host. There is a considerable amount of work in the search of more promising molecular targets for drug design. However, the chemotherapy for this disease remains unsolved. It is based on old and fairly not specific drugs associated with long-term treatments, severe side effects, drug resistance, and different strains' susceptibility. Herein, a thorough analysis of selected molecular targets is described in terms of their potential usefulness for drug design. Therefore, rational approaches to the chemotherapeutic control of American trypanosomiasis describing some useful metabolic pathways are covered. Enzymes involved in ergosterol biosynthesis (squalene synthase, HMG-CoA reductase, farnesyl diphosphate synthase (FPPS), sterol 24-methyltransferase, and sterol 14α-demethylase), trypanothione system (glutathionyl-spermidine synthetase, trypanothione synthetase, and trypanothione reductase), cysteine proteases, transsialidase, and so on are discussed. The design of specific inhibitors of these metabolic activities as possible means of controlling the parasites without damaging the hosts is presented. Different compounds can behave as TryR inhibitors when turning into reactive radical speciesthrough the reduction single-electron step [83,91]. Within these structures, 1, 4 naphthoquinones and nitrofurans have been largely studied [92,93]. The most potent derivative of 1,4 naphthoquinone was a quinone-coumarin hybrid [51] despite showing toxicity against rat skeletal myoblasts [94].Between nitrofurans compounds, several 5-nitrofuroic acid derivatives have been synthesized and evaluated against T. cruzi. The best compound was 5-nitro-furan-2-carboxylic acid dibenzyl amide [52], which it significantly increased the trypanocidal nifurtimox activity being TryTR your molecular target [95]. ConclusionsCurrently, the chemotherapy of American trypanosomiasis remains a serious problem in the field of neglected tropical diseases. There are no vaccines, and chemotherapy is limited to old drugs, which present important drawbacks. Taking into account that this disease is associated with poor populations and bad housing conditions, pharmaceutical companies have no economic motivations. Therefore, all efforts to the development of new drugs must be made by academic and/or governmental institutions and new chemotherapies are needed urgently. In order to search new, safer and efficient drugs for the Chagas' treatment, an overview of possible molecular targets based on specific features of the biochemistry of Trypanosoma cruzi was given. Although there are numerous potentially valid targets, only the more representative ones were discussed here. Furthermore, some of t...

show abstract

“…The disease has a short acute phase spanning one or two months, generally asymptomatic, followed by a long silent period [1], and finally the patients enter the chronic phase in which around two-thirds of them remain in an asymptomatic indeterminate stage, and one-third become symptomatic, with the appearance of severe cardiovascular disorders, and/or gastrointestinal dysfunctions (with visceromegaly) [1][2][3]. Despite the fact that intense efforts are being made toward the development of novel drugs for the treatment of Chagas' disease, only the nitro derivatives nifurtimox and benznidazole (BZN) are currently in use, albeit with restrictions due to the undesirable side effects on patients and the uncertain efficacy during the chronic phase of the disease [4][5][6][7][8]. In addition, the search for drugs for the chronic phase has been hindered by the lack of animal models reproducing the human disease.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The in vivo trypanocidal effect of the diterpene 5-epi-icetexone obtained from Salvia gilliesii

Lozano

Strauss

Spina

et al. 2016

Parasitology International

View full text Add to dashboard Cite

The search for new compounds with trypanocidal activity is crucial for the treatment of Chagas' disease. Previous in vitro studies have shown that the diterpene 5-epi-icetexone (ICTX) is active against Trypanosoma cruzi. The aim of this work was to evaluate the effect of ICTX on the parasites in infected mice, in an experimental model that mimics the acute phase of the disease. Swiss albino mice were infected with T. cruzi and treated daily with 10mg/kg/day ICTX (i.p.). Infected mice and mice injected with either saline or the vehicle DMSO were used as controls. Animals' survival and parasitemia were monitored once a week and histological studies were made at necropsy by the 5th week after infection. It was observed that the administration of ICTX increased the survival of mice infected, and induced a significant decrease in the parasitemia, as compared to controls. A similar protective effect was observed when animals were treated orally with benznidazole (BZN, used as a control of antiparasitic effect). By the 5th week post-infection, the presence of amastigote nests was observed within the fibers of the cardiac and skeletal muscle in controls, but not in animals treated with either ICTX or BZN. In addition, inflammatory infiltrates were observed in the tissues of controls, but not in animals treated with the drugs. We conclude that ICTX has an antiparasitic effect against T. cruzi, thus constituting an interesting option for the treatment of Chagas' disease, alone or combined with other drugs.

show abstract

A Decade of Targets and Patented Drugs for Chemotherapy of Chagas Disease

Cited by 26 publications

References 311 publications

Essential multimeric enzymes in kinetoplastid parasites: A host of potentially druggable protein-protein interactions

Essential multimeric enzymes in kinetoplastid parasites: A host of potentially druggable protein-protein interactions

New Approaches for Chagas’ Disease Chemotherapy

The in vivo trypanocidal effect of the diterpene 5-epi-icetexone obtained from Salvia gilliesii

Contact Info

Product

Resources

About