From proteins to molecular targets: Trypanosoma cruzi proteomic insights in drug development

Brunoro, Giselle V-F; Caminha, Marcelle Almeida; Menna-Barreto, Rubem F. S.

doi:10.21775/9781910190838.01

Cited by 3 publications

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“…Additionally, in starved T. cruzi , TcVps15 overexpression increased the number of autophagosomes, suggesting a regulatory role for this enzyme in the control of TcVps34 enzymatic activity (Figs 2 and 3) 119 . Curiously, a great number of large-scale proteomic studies in trypanosomatids did not find evidence of autophagic proteins under nutritional stress (during metacyclogenesis, for example), strongly suggesting the inability to find homologues of Atgs in these parasites 120 .…”

Section: Death Processes In Trypanosomatidsmentioning

confidence: 99%

Cell death pathways in pathogenic trypanosomatids: lessons of (over)kill

Menna-Barreto

2019

Cell Death Dis

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Especially in tropical and developing countries, the clinically relevant protozoa Trypanosoma cruzi (Chagas disease), Trypanosoma brucei (sleeping sickness) and Leishmania species (leishmaniasis) stand out and infect millions of people worldwide leading to critical social-economic implications. Low-income populations are mainly affected by these three illnesses that are neglected by the pharmaceutical industry. Current anti-trypanosomatid drugs present variable efficacy with remarkable side effects that almost lead to treatment discontinuation, justifying a continuous search for alternative compounds that interfere with essential and specific parasite pathways. In this scenario, the triggering of trypanosomatid cell death machinery emerges as a promising approach, although the exact mechanisms involved in unicellular eukaryotes are still unclear as well as the controversial biological importance of programmed cell death (PCD). In this review, the mechanisms of autophagy, apoptosis-like cell death and necrosis found in pathogenic trypanosomatids are discussed, as well as their roles in successful infection. Based on the published genomic and proteomic maps, the panel of trypanosomatid cell death molecules was constructed under different experimental conditions. The lack of PCD molecular regulators and executioners in these parasites up to now has led to cell death being classified as an unregulated process or incidental necrosis, despite all morphological evidence published. In this context, the participation of metacaspases in PCD was also not described, and these proteases play a crucial role in proliferation and differentiation processes. On the other hand, autophagic phenotype has been described in trypanosomatids under a great variety of stress conditions (drugs, starvation, among others) suggesting that this process is involved in the turnover of damaged structures in the protozoa and is not a cell death pathway. Death mechanisms of pathogenic trypanosomatids may be involved in pathogenesis, and the identification of parasite-specific regulators could represent a rational and attractive alternative target for drug development for these neglected diseases.

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Section: Death Processes In Trypanosomatidsmentioning

confidence: 99%

Cell death pathways in pathogenic trypanosomatids: lessons of (over)kill

Menna-Barreto

2019

Cell Death Dis

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“…Preclinical in silico combined to in vitro assays represents an essential step for the recognition of T. cruzi drug targets, generating knowledge about the metabolism, biochemical pathways, or biological processes allowing the target validation. In this way, the identification of selective targets comprises a logical startpoint to the reduction of the side effects in the hosts [153,163]. Ultrastructural observations can predict the potential primary cellular targets due to their earlier alterations triggered by pharmacologic stimuli, helping the prospection of molecular modes of action of antiparasitic agents [141,174].…”

Section: Discussionmentioning

confidence: 99%

“…The evaluation of the proteomic profile in trypanosomatids is particularly interesting because these protozoa exhibit open reading frames in long polycistronic regions, and the regulation of gene expression occurs only post-transcriptionally, justifying the importance on monitoring the protein expression by proteomic approach [153]. This section will focus on proteomic analysis of parasite forms dwelling in mammalian hosts.…”

Section: Proteomic Insights For the Target Identification In The Paramentioning

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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Section: Discussionmentioning

confidence: 99%

Biology of Trypanosoma cruzi

Souza¹

2019

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He is a member of several scientific societies as well as academies of science and medicine. He is also a member of the editorial board of several international journals in the area of parasitology. He has published more than 600 scientific papers and 100 articles in many prestigious Brazilian newspapers. Contents Preface XIII Section 1 Basic Biology Chapter 1 Introductory Chapter: Biology of Trypanosoma cruzi by Wanderley de Souza Chapter 2 Life Cycle of Trypanosoma cruzi in the Invertebrate and the Vertebrate Hosts by Kenechukwu C.

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From proteins to molecular targets: Trypanosoma cruzi proteomic insights in drug development

Cited by 3 publications

References 0 publications

Cell death pathways in pathogenic trypanosomatids: lessons of (over)kill

Cell death pathways in pathogenic trypanosomatids: lessons of (over)kill

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

Biology of Trypanosoma cruzi

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