Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction

Li, Mengqiao; Gaussmann, Stefan; Tippler, Bettina; Ott, Julia; Popowicz, Grzegorz M.; Schliebs, Wolfgang; Sattler, Michael; Erdmann, Ralf; Kalel, Vishal C.

doi:10.3389/fcell.2021.737159

Cited by 6 publications

(5 citation statements)

References 52 publications

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“…Suramin can inhibit numerous enzymes, namely T. b. glycolytic enzymes (hexokinase, aldolase, phosphoglycerate kinase, glycerol-3-phosphate dehydrogenase). The glycolytic enzymes are inside the glycosomes of the parasite, and it is still unclear how suramin could penetrate the membrane or if it could bind to glycolytic enzymes in the cytosol before their entrance in the glycosomes [ 24 ]. Alternative targets proposed for the trypanocidal effect of suramin are glycerophosphate oxidase, a serine oligopeptidase termed OP-Tb, the RNA-editing ligase REL1 of the trypanosome’s kinetoplast.…”

Section: Current Treatments and Therapeutic Challenges For Hatmentioning

confidence: 99%

“…Its modest in vitro potency against T. b . (IC 50 around 0.6 µM) was offset by good in vivo pharmacokinetic properties, giving a 100% cure in a mouse model of stage 2 disease following an oral dosing of 25 mg/kg once a day for seven days [ 24 ]. Preclinical testing showed acceptable toxicity in mice or dogs with a concentration of no observed adverse event limit (NOAEL) of 15 mg/kg.…”

Section: Recent Clinical Candidate Drugs For Hatmentioning

confidence: 99%

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Current Treatments to Control African Trypanosomiasis and One Health Perspective

et al. 2022

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Human African Trypanosomiasis (HAT, sleeping sickness) and Animal African Trypanosomiasis (AAT) are neglected tropical diseases generally caused by the same etiological agent, Trypanosoma brucei. Despite important advances in the reduction or disappearance of HAT cases, AAT represents a risky reservoir of the infections. There is a strong need to control AAT, as is claimed by the European Commission in a recent document on the reservation of antimicrobials for human use. Control of AAT is considered part of the One Health approach established by the FAO program against African Trypanosomiasis. Under the umbrella of the One Health concepts, in this work, by analyzing the pharmacological properties of the therapeutic options against Trypanosoma brucei spp., we underline the need for clearer and more defined guidelines in the employment of drugs designed for HAT and AAT. Essential requirements are addressed to meet the challenge of drug use and drug resistance development. This approach shall avoid inter-species cross-resistance phenomena and retain drugs therapeutic activity.

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Section: Current Treatments and Therapeutic Challenges For Hatmentioning

confidence: 99%

Section: Recent Clinical Candidate Drugs For Hatmentioning

confidence: 99%

Current Treatments to Control African Trypanosomiasis and One Health Perspective

et al. 2022

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“…Recently, breakthroughs have been achieved with the development of PFK inhibitors that cure infected mice from a T. brucei infection without apparent toxic effect on the animals (McNae et al, 2021) and compounds that provided proof of concept for glycosomal peroxin interacas drug targets. Library screenings yielded compounds that interfere with the PEX5-PEX14 and PEX3-PEX19 in T. brucei glycosomes, affecting glycosome biogenesis and viability of cultured trypanosomes with no apparent or little effect on cultured human cells (Banerjee et al, 2021;Dawidowski et al, 2017;Li et al, 2021). Will such compounds lead in due time to drugs that can be used for the treatment of one or more of the human neglected diseases or veterinary diseases caused by trypanosomatids?…”

Section: Discussionmentioning

confidence: 99%

“…Library screenings yielded compounds that interfere with the PEX5‐PEX14 and PEX3‐PEX19 interaction in T . brucei glycosomes, affecting glycosome biogenesis and viability of cultured trypanosomes with no apparent or little effect on cultured human cells (Banerjee et al, 2021; Dawidowski et al, 2017; Li et al, 2021). Will such compounds lead in due time to drugs that can be used for the treatment of one or more of the human neglected diseases or veterinary diseases caused by trypanosomatids?…”

Section: Discussionmentioning

confidence: 99%

Biogenesis and metabolic homeostasis of trypanosomatid glycosomes: New insights and new questions

Michels

Gualdrón‐López

2022

J Eukaryotic Microbiology

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Kinetoplastea and Diplonemea possess peroxisome‐related organelles that, uniquely, contain most of the enzymes of the glycolytic pathway and are hence called glycosomes. Enzymes of several other core metabolic pathways have also been located in glycosomes, in addition to some characteristic peroxisomal systems such as pathways of lipid metabolism. A considerable amount of research has been performed on glycosomes of trypanosomes since their discovery four decades ago. Not only the role of the glycosomal enzyme systems in the overall cell metabolism appeared to be unique, but also the organelles display remarkable features regarding their biogenesis and structural properties. These features are similar to those of the well‐studied peroxisomes of mammalian and plant cells and yeasts yet exhibit also differences reflecting the large evolutionary distance between these protists and the representatives of other major eukaryotic lineages. Despite all research performed, many questions remain about various properties and the biological roles of glycosomes and peroxisomes. Here, we review the current knowledge about glycosomes, often comparing it with information about peroxisomes. Furthermore, we highlight particularly many questions that remain about the biogenesis, and the heterogeneity in structure and content of these enigmatic organelles, and the properties of their boundary membrane.

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“…By interfering with these peroxins, the import of matrix proteins and in turn the biogenesis of glycosomes will be blocked. This will disrupt various glycosome-associated metabolic pathways, resulting in parasite death (Kalel et al 2017, Li et al 2021). Given the significance of PMPs as described above, an inventory of glycosomal membrane proteins will provide insights into their functional importance, translocation mechanisms, and role in organelle biogenesis.…”

Section: Introductionmentioning

confidence: 99%

High confidence glycosomal membrane protein inventory unveils trypanosomal Peroxin PEX15

Krishna,

Das,

Hohnen

et al. 2023

Preprint

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Trypanosomatids are a subgroup of kinetoplastids that share the features of harboring a kinetoplast and a flagellum. Infections by these parasites pose a major concern to human health, causing diseases like Chagas disease, Human African Trypanosomiasis (HAT), and Leishmaniasis, affecting over 12 million people worldwide. Trypanosomatid parasites possess a unique peroxisome-like organelle called Glycosomes, which are essential for parasite survival. Formation and function of glycosomes depend on the cytosolic receptors and various peroxisomal membrane proteins (PMPs). These PMPs either act as Peroxin (PEX) proteins in the glycosome biogenesis or play a crucial role in facilitating the movement of solutes/molecules across the glycosomal membrane. Given the significance of PMPs, an inventory of the glycosomal membrane proteins will provide insights into their functional importance, and also aid in the identification of unknown or parasite specific Peroxins. In this study, we describe the isolation of glycosomes, its membrane protein enrichment, and mass-spectrometry-based proteomic analysis followed by protein-correlation profiling to establish a high-confidence inventory of 57 glycosomal membrane proteins, with 44 additional putative candidates. Four novel proteins from this inventory were validated, which includes two tail-anchored (TA) proteins, a homolog of human PXMP4, and a Macrodomain containing protein. Using a structure-based approach, we identified that the novel TA protein is the long-soughtTrypanosomaPEX15. Despite its low sequence similarity, it exhibits structural and topological similarities with its yeast (Pex15) and human counterpart (PEX26). We show that PEX15 is an integral membrane protein that localizes to the glycosome and interacts with PEX6. RNAi knockdown of PEX15 in bloodstream form (BSF) trypanosomes demonstrates that it is essential for glycosome biogenesis. Considering the low degree of conservation with its human counterpart, PEX15 is a promising molecular target for drug development.

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Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction

Cited by 6 publications

References 52 publications

Current Treatments to Control African Trypanosomiasis and One Health Perspective

Current Treatments to Control African Trypanosomiasis and One Health Perspective

Biogenesis and metabolic homeostasis of trypanosomatid glycosomes: New insights and new questions

High confidence glycosomal membrane protein inventory unveils trypanosomal Peroxin PEX15

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