Inhibition of Isoleucyl-tRNA Synthetase as a Potential Treatment for Human African Trypanosomiasis

Cestari, Igor; Stuart, Kenneth

doi:10.1074/jbc.m112.447441

Cited by 21 publications

(28 citation statements)

References 38 publications

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“…T. brucei parasitemia in doxycycline-treated mice was initially detected at day 2 postinfection and increased rapidly, reaching ϳ3.0 ϫ 10 8 parasites/ml of blood on day 4 postinfection (Fig. 6f), which resembles the parasitemia achieved during infection by the wild-type parasite (24). However, in mice that did not receive doxycycline, the parasitemia was delayed, and it rose more slowly in untreated mice than in doxycycline-treated mice, suggesting that mcp2 expression is required for efficient parasite infection (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…2 and Table 2). Indeed, RNAi knockdown of all aaRS genes tested to date resulted in growth inhibition of either procyclic or bloodstream forms in vitro (Table 2) and also prevented infection of mice (24). Overall, T. brucei has all aaRS genes needed to aminoacylate the 20 aminoacyl-tRNAs required for protein synthesis.…”

Section: Resultsmentioning

confidence: 99%

“…Both cytoplasmic and mitochondrial translation are essential for T. brucei bloodstream and procyclic forms (27,70,71), and the dually localized enzymes may be especially attractive since their inhibition may block protein synthesis in both cellular compartments. For example, we showed that inhibition of IleRS, which is dually localized in the cytoplasm and mitochondrion, cures mice infected with T. brucei (24).…”

Section: Discussionmentioning

confidence: 99%

“…and T. cruzi. Few aaRSs have been characterized in T. brucei, and most of the genetic studies have been conducted on the insect stage of the parasite (24)(25)(26)(27)(28)(29)(30)(31). Although in T. brucei translation takes place in both the cytoplasm and the mitochondria, only 24 genes have been identified in the genome as potentially encoding aaRSs (32).…”

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confidence: 99%

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A Multiple Aminoacyl-tRNA Synthetase Complex That Enhances tRNA-Aminoacylation in African Trypanosomes

Cestari

Kalidas

Monnerat

et al. 2013

Molecular and Cellular Biology

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The genes for all cytoplasmic and potentially all mitochondrial aminoacyl-tRNA synthetases (aaRSs) were identified, and all those tested by RNA interference were found to be essential for the growth of Trypanosoma brucei. Some of these enzymes were localized to the cytoplasm or mitochondrion, but most were dually localized to both cellular compartments. Cytoplasmic T. brucei aaRSs were organized in a multiprotein complex in both bloodstream and procyclic forms. The multiple aminoacyl-tRNA synthetase (MARS) complex contained at least six aaRS enzymes and three additional non-aaRS proteins. Steady-state kinetic studies showed that association in the MARS complex enhances tRNA-aminoacylation efficiency, which is in part dependent on a MARS complex-associated protein (MCP), named MCP2, that binds tRNAs and increases their aminoacylation by the complex. Conditional repression of MCP2 in T. brucei bloodstream forms resulted in reduced parasite growth and infectivity in mice. Thus, association in a MARS complex enhances tRNA-aminoacylation and contributes to parasite fitness. The MARS complex may be part of a cellular regulatory system and a target for drug development.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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A Multiple Aminoacyl-tRNA Synthetase Complex That Enhances tRNA-Aminoacylation in African Trypanosomes

Cestari

Kalidas

Monnerat

et al. 2013

Molecular and Cellular Biology

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“…Almost all aaRSs in the T. brucei genome are single copy and thus must serve dual roles in the cytosol and mitochondria; TrpRS, LysRS, and AspRS are three notable exceptions where separate cytosolic and mitochondrial genes have been identified (24)(25)(26). Several T. brucei aaRS genes have been reported to be essential in parasites in either the insect stage (procyclic) or the mammalian stage (21,(25)(26)(27)(28)(29)(30). Several groups have also reported the identification of MetRS, IleRS, and LeuRS inhibitors with antitrypanosome activity (30)(31)(32)(33)(34)(35).…”

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confidence: 99%

Genetic Validation of Aminoacyl-tRNA Synthetases as Drug Targets in Trypanosoma brucei

et al. 2014

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bHuman African trypanosomiasis (HAT) is an important public health threat in sub-Saharan Africa. Current drugs are unsatisfactory, and new drugs are being sought. Few validated enzyme targets are available to support drug discovery efforts, so our goal was to obtain essentiality data on genes with proven utility as drug targets. Aminoacyl-tRNA synthetases (aaRSs) are known drug targets for bacterial and fungal pathogens and are required for protein synthesis. Here we survey the essentiality of eight Trypanosoma brucei aaRSs by RNA interference (RNAi) gene expression knockdown, covering an enzyme from each major aaRS class: valyl-tRNA synthetase (ValRS) (class Ia), tryptophanyl-tRNA synthetase (TrpRS-1) (class Ib), arginyl-tRNA synthetase (ArgRS) (class Ic), glutamyl-tRNA synthetase (GluRS) (class 1c), threonyl-tRNA synthetase (ThrRS) (class IIa), asparaginyltRNA synthetase (AsnRS) (class IIb), and phenylalanyl-tRNA synthetase (␣ and ␤) (PheRS) (class IIc). Knockdown of mRNA encoding these enzymes in T. brucei mammalian stage parasites showed that all were essential for parasite growth and survival in vitro. The reduced expression resulted in growth, morphological, cell cycle, and DNA content abnormalities. ThrRS was characterized in greater detail, showing that the purified recombinant enzyme displayed ThrRS activity and that the protein localized to both the cytosol and mitochondrion. Borrelidin, a known inhibitor of ThrRS, was an inhibitor of T. brucei ThrRS and showed antitrypanosomal activity. The data show that aaRSs are essential for T. brucei survival and are likely to be excellent targets for drug discovery efforts.

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The current drug discovery landscape for trypanosomiasis and leishmaniasis: Challenges and strategies to identify drug targets

Altamura

Rajesh

Catta-Preta

et al. 2020

Drug Development Research

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Human trypanosomiasis and leishmaniasis are vector‐borne neglected tropical diseases caused by infection with the protozoan parasites Trypanosoma spp. and Leishmania spp., respectively. Once restricted to endemic areas, these diseases are now distributed worldwide due to human migration, climate change, and anthropogenic disturbance, causing significant health and economic burden globally. The current chemotherapy used to treat these diseases has limited efficacy, and drug resistance is spreading. Hence, new drugs are urgently needed. Phenotypic compound screenings have prevailed as the leading method to discover new drug candidates against these diseases. However, the publication of the complete genome sequences of multiple strains, advances in the application of CRISPR/Cas9 technology, and in vivo bioluminescence‐based imaging have set the stage for advancing target‐based drug discovery. This review analyses the limitations of the narrow pool of available drugs presently used for treating these diseases. It describes the current drug‐based clinical trials highlighting the most promising leads. Furthermore, the review presents a focused discussion on the most important biological and pharmacological challenges that target‐based drug discovery programs must overcome to advance drug candidates. Finally, it examines the advantages and limitations of modern research tools designed to identify and validate essential genes as drug targets, including genomic editing applications and in vivo imaging.

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Inhibition of Isoleucyl-tRNA Synthetase as a Potential Treatment for Human African Trypanosomiasis

Cited by 21 publications

References 38 publications

A Multiple Aminoacyl-tRNA Synthetase Complex That Enhances tRNA-Aminoacylation in African Trypanosomes

A Multiple Aminoacyl-tRNA Synthetase Complex That Enhances tRNA-Aminoacylation in African Trypanosomes

Genetic Validation of Aminoacyl-tRNA Synthetases as Drug Targets in Trypanosoma brucei

The current drug discovery landscape for trypanosomiasis and leishmaniasis: Challenges and strategies to identify drug targets

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