The thermal proteome stability profile of Trypanosoma cruzi in epimastigote and trypomastigote life stages

Rosa-Fernandes, Lívia; Mule, Simon Ngao; Oliveira, Gilberto Santos de; Manchola, Nubia Carolina; Santiago, Verônica Feijoli; Colli, Walter; Wrenger, Carsten; Alves, Maria Júlia M.; Palmisano, Giuseppe

doi:10.1016/j.jprot.2021.104339

Cited by 7 publications

(4 citation statements)

References 109 publications

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“…In this sense, Target-Pathogen (http://target.sbg.qb.fcen.uba.ar) is a unique resource that combines structural druggability datasets, essentiality analysis, metabolic context, genomic and expression data to rank proteins according to their potential to be used as novel targets. Previous reports from our and other groups have selected and prioritized molecular targets of several relevant pathogens such as Mycobacterium tuberculosis (Defelipe et al, 2016), Klebsiella pneumoniae (Ramos et al, 2018;Serral et al, 2021, Serral et al, 2022, Bartonella bacilliformis (Farfán-López et al, 2020), Trypanosoma cruzi (Osorio-Méndez andCevallos, 2018;Coutinho et al, 2021) and Schistosoma mansoni (Lobo-Silva et al, 2020) using Target-Pathogen.…”

Section: Introductionmentioning

confidence: 99%

Integrating diverse layers of omic data to identify novel drug targets in Listeria monocytogenes

Palumbo

Sosa²,

Castello³

et al. 2022

Front. Drug. Discov.

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Listeriamonocytogenes (Lm) is a Gram-positive bacillus responsible for listeriosis in humans. Listeriosis has become a major foodborne illness in recent years. This illness is mainly associated with the consumption of contaminated food and ready-to-eat products. Recently, Lm has developed resistances to a broad range of antimicrobials, including those used as the first choice of therapy. Moreover, multidrug-resistant strains have been detected in clinical isolates and settings associated with food processing. This scenario punctuates the need for novel antimicrobials against Lm. On the other hand, increasingly available omics data for diverse pathogens has created new opportunities for rational drug discovery. Identification of an appropriate molecular target is currently accepted as a critical step of this process. In this work, we generated multiple layers of omics data related to Lm, aiming to prioritize proteins that could serve as attractive targets for antimicrobials against L. monocytogenes. We generated genomic, transcriptomic, metabolic, and protein structural information, and this data compendium was integrated onto a freely available web server (Target Pathogen). Thirty targets with desirable features from a drug development point of view were shortlisted. This set of target proteins participates in key metabolic processes such as fatty acid, pentose, rhamnose, and amino acids metabolism. Collectively, our results point towards novel targets for the control of Lm and related bacteria. We invite researchers working in the field of drug discovery to follow up experimentally on our revealed targets.

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Section: Introductionmentioning

confidence: 99%

Integrating diverse layers of omic data to identify novel drug targets in Listeria monocytogenes

Palumbo

Sosa²,

Castello³

et al. 2022

Front. Drug. Discov.

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“…qb.fcen.uba.ar) (Sosa et al, 2018) is a unique resource that helps to achieve this task, combining structural druggability datasets, essentiality analysis, metabolic context, genomic, and expression data to rank gene/proteins according to their potential as novel antimicrobial targets. Previous reports, from our and other groups, used this tool to select and prioritize molecular targets of several relevant pathogens such as M. tuberculosis (Defelipe et al, 2016), K. pneumoniae (Ramos et al, 2018;Serral et al, 2022), Bartonella bacilliformis (Farfán-López et al, 2020;Serral et al, 2021), Trypanosoma cruzi (Osorio-Méndez et al, 2016;Coutinho et al, 2021) and Schistosoma mansoni (Lobo-Silva et al , 2020). Once the target is selected, the challenge moves to the identification of a small molecule that can inhibit the protein target's function, allows further pharmacological validation of the target, and ultimately drives the development of a new antibiotic.…”

Section: Introductionmentioning

confidence: 99%

From drugs to targets: Reverse engineering the virtual screening process on a proteomic scale

Schottlender

Prieto²,

Palumbo³

et al. 2022

Front. Drug. Discov.

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Phenotypic screening is a powerful technique that allowed the discovery of antimicrobials to fight infectious diseases considered deadly less than a century ago. In high throughput phenotypic screening assays, thousands of compounds are tested for their capacity to inhibit microbial growth in-vitro. After an active compound is found, identifying the molecular target is the next step. Knowing the specific target is key for understanding its mechanism of action, and essential for future drug development. Moreover, this knowledge allows drug developers to design new generations of drugs with increased efficacy and reduced side effects. However, target identification for a known active compound is usually a very difficult task. In the present work, we present a powerful reverse virtual screening strategy, that can help researchers working in the drug discovery field, to predict a set of putative targets for a compound known to exhibit antimicrobial effects. The strategy combines chemical similarity methods, with target prioritization based on essentiality data, and molecular-docking. These steps can be tailored according to the researchers’ needs and pathogen’s available information. Our results show that using only the chemical similarity approach, this method is capable of retrieving potential targets for half of tested compounds. The results show that even for a low chemical similarity threshold whenever domains are retrieved, the correct domain is among those retrieved in more than 80% of the queries. Prioritizing targets by an essentiality criteria allows us to further reduce, up to 3–4 times, the number of putative targets. Lastly, docking is able to identify the correct domain ranked in the top two in about two thirds of cases. Bias docking improves predictive capacity only slightly in this scenario. We expect to integrate the presented strategy in the context of Target Pathogen database to make it available for the wide community of researchers working in antimicrobials discovery.

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“…[4,6,7] The T. cruzi parasite is transmitted to humans by domiciled hematophagous triatomine vector insects, mainly Triatoma infestans and Rhodnius prolixus. [8,9] Although recent vector control programs such as the National Program for the Control of Chagas Disease have helped to reduce infection rates in endemic areas, non-vector transmission routes such as contaminated food, blood transfusions and congenital transmission are becoming most common. [3,4,7,9,10] Vector transmission occurs when the insect feeds on the blood of an infected mammal and ingests the circulating trypomastigote form of T. cruzi.…”

Section: Introductionmentioning

confidence: 99%

“…[6,9,[11][12][13] There is no vaccine against Chagas disease and the available treatment, benznidazole and nifurtimox, have limited efficacy in the chronic phase of the disease and exhibit serious side effects. [8,9] For this reason, the search for new drugs for the treatment of Chagas disease is extremely relevant. And natural products stand out as a promising source of new drugs, since so many therapeutic drugs are natural products or inspired by their chemical structures.…”

Section: Introductionmentioning

confidence: 99%

Natural Products from Annonaceae as Potential Antichagasic Agents

et al. 2022

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Chagas disease, a neglected tropical disease, is endemic in 21 Latin American countries and particularly prevalent in Brazil. Chagas disease has drawn more attention in recent years due to its expansion into non-endemic areas. The aim of this work was to computationally identify and experimentally validate the natural products from an Annonaceae family as antichagasic agents. Through the ligand-based virtual screening, we identified 57 molecules with potential activity against the epimastigote form of T. cruzi. Then, 16 molecules were analyzed in the in vitro study, of which, six molecules displayed previously unknown antiepimastigote activity. We also evaluated these six molecules for trypanocidal activity. We observed that all six molecules have potential activity against the amastigote form, but no molecules were active against the trypomastigote form. 13-Epicupressic acid seems to be the most promising, as it was predicted as an active compound in the in silico study against the amastigote form of T. cruzi, in addition to having in vitro activity against the epimastigote form.

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The thermal proteome stability profile of Trypanosoma cruzi in epimastigote and trypomastigote life stages

Cited by 7 publications

References 109 publications

Integrating diverse layers of omic data to identify novel drug targets in Listeria monocytogenes

Integrating diverse layers of omic data to identify novel drug targets in Listeria monocytogenes

From drugs to targets: Reverse engineering the virtual screening process on a proteomic scale

Natural Products from Annonaceae as Potential Antichagasic Agents

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