Identification of Specific Inhibitors of Trypanosoma cruzi Malic Enzyme Isoforms by Target-Based HTS

Ranzani, Américo Tavares; Nowicki, Cristina; Wilkinson, Shane R.; Cordeiro, Artur T.

doi:10.1177/2472555217706649

Cited by 15 publications

(29 citation statements)

References 31 publications

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“…Silence of ME1 significantly suppressed tumor growth and induced elevated cell apoptosis. Importantly, a recent report has revealed a panel of small molecules that could inhibit activities of malic enzymes (17). However, further studies are needed to confirm the clinical benefit of these inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…In human cells, malic enzymes are encoded by three homologous genes (15,16), including ME1, which is located in the cytoplasm and enzymic activities require NADP; malic enzyme 2 (ME2), which is located in the mitochondrion and enzymic activities require NAD; and ME3, which is located in the mitochondrion and enzymic activities require NADP. These enzymes are widely distributed in nature and have highly conserved sequences and similar structural topologies across different species, suggesting that they have important biological functions (17).…”

Section: Introductionmentioning

confidence: 99%

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ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis

et al. 2018

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Genomic alterations of tumor suppressorsoften encompass collateral protein-coding genes that create therapeutic vulnerability to further inhibition of their paralogs. Here, we report that () is frequently hemizygously codeleted with in gastric cancer. Its isoenzyme ME1 was upregulated to replenish the intracellular reducing equivalent NADPH and to maintain redox homeostasis. Knockdown of ME1 significantly depleted NADPH, induced high levels of reactive oxygen species (ROS), and ultimately cell apoptosis under oxidative stress conditions, such as glucose starvation and anoikis, in ME2-underexpressed cells. Moreover, ME1 promoted tumor growth, lung metastasis, and peritoneal dissemination of gastric cancer Intratumoral injection of siRNA significantly suppressed tumor growth in cell lines and patient-derived xenograft-based models. Mechanistically, was transcriptionally upregulated by ROS in an ETV4-dependent manner. Overexpression of ME1 was associated with shorter overall and disease-free survival in gastric cancer. Altogether, our results shed light on crucial roles of ME1-mediated production of NADPH in gastric cancer growth and metastasis. These findings reveal the role of malic enzyme in growth and metastasis. http://cancerres.aacrjournals.org/content/canres/78/8/1972/F1.large.jpg .

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis

et al. 2018

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“…donovani activities reported for this compound, considering the global similarities of enzymes within CYP51 family [40, 41]. Although involved in other studies as part of the GSK CHAGAS Box [42], no further information is currently available from the evaluation of TCMDC-143620 against other molecular targets, except for our previous cruzipain study [24] where it was found to be inactive (~7,5% of cruzipain inhibition at 25 μM). A complete profile of the off-target activity of TCMDC-143620 would be critical for future optimization efforts in order to achieve a suitable M32 MCPs probe from this compound.…”

Section: Discussionmentioning

confidence: 99%

Potent and selective inhibitors for M32 metallocarboxypeptidases identified from high-throughput screening of anti-kinetoplastid chemical boxes

et al. 2019

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Enzymes of the M32 family are Zn-dependent metallocarboxypeptidases (MCPs) widely distributed among prokaryotic organisms and just a few eukaryotes including Trypanosoma brucei and Trypanosoma cruzi , the causative agents of sleeping sickness and Chagas disease, respectively. These enzymes are absent in humans and several functions have been proposed for trypanosomatid M32 MCPs. However, no synthetic inhibitors have been reported so far for these enzymes. Here, we present the identification of a set of inhibitors for Tc MCP-1 and Tb MCP-1 (two trypanosomatid M32 enzymes sharing 71% protein sequence identity) from the GlaxoSmithKline HAT and CHAGAS chemical boxes; two collections grouping 404 compounds with high antiparasitic potency, drug-likeness, structural diversity and scientific novelty. For this purpose, we adapted continuous fluorescent enzymatic assays to a medium-throughput format and carried out the screening of both collections, followed by the construction of dose-response curves for the most promising hits. As a result, 30 micromolar-range inhibitors were discovered for one or both enzymes. The best hit, TCMDC-143620, showed sub-micromolar affinity for Tc MCP-1, inhibited Tb MCP-1 in the low micromolar range and was inactive against angiotensin I-converting enzyme (ACE), a potential mammalian off-target structurally related to M32 MCPs. This is the first inhibitor reported for this family of MCPs and considering its potency and specificity, TCMDC-143620 seems to be a promissory starting point to develop more specific and potent chemical tools targeting M32 MCPs from trypanosomatid parasites.

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“…Ranzani et al [124] have screened 30,000 compounds using the two-independent HTS strategies on infected cells and identified specific inhibitors that target the T. cruzi malic enzyme (TcMEs), which have trypanocidal activity against the intracellular stage of this pathogen in vitro.…”

Section: Phenotypic Approachesmentioning

confidence: 99%

Advances in preclinical approaches to Chagas disease drug discovery

Villalta

Rachakonda

2019

Expert Opinion on Drug Discovery

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Introduction Chagas disease affects 8–10 million people worldwide, mainly in Latin America. The current therapy for Chagas disease is limited to nifurtimox and benznidazole, which are effective in treating only the acute phase of the disease but with severe side effects. Therefore, there is an unmet need for new drugs and for the exploration of innovative approaches which may lead to the discovery of new effective and safe drugs for its treatment. Areas covered The authors report and discuss recent approaches including structure-based design that have led to the discovery of new promising small molecule candidates for Chagas disease which affect prime targets that intervene in the sterol pathway of T. cruzi. Other trypanosome targets, phenotypic screening, the use of artificial intelligence and the challenges with Chagas disease drug discovery are also discussed. Expert opinion The application of recent scientific innovations to the field of Chagas disease have led to the discovery of new promising drug candidates for Chagas disease. Phenotypic screening brought new hits and opportunities for drug discovery. Artificial intelligence also has the potential to accelerate drug discovery in Chagas disease and further research into this is warranted.

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Identification of Specific Inhibitors of Trypanosoma cruzi Malic Enzyme Isoforms by Target-Based HTS

Cited by 15 publications

References 31 publications

ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis

ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis

Potent and selective inhibitors for M32 metallocarboxypeptidases identified from high-throughput screening of anti-kinetoplastid chemical boxes

Advances in preclinical approaches to Chagas disease drug discovery

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