Characterization of an Atypical Trypanosoma brucei Hsp70 Demonstrates Its Cytosolic-Nuclear Localization and Modulation by Quercetin and Methylene Blue

Burger, Adélle; Macucule-Tinga, Paula; Bentley, Stephen; Ludewig, Michael H.; Mhlongo, Ndumiso N.; Shonhai, Addmore; Boshoff, Aileen

doi:10.3390/ijms22136776

Cited by 3 publications

(3 citation statements)

References 47 publications

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“…Co-chaperones of T. brucei Hsp90 were recently identified, and it is possible that chaperone/co-chaperone interactions could be pursued as potential drug targets [251]. Molecular chaperones, in particular the Hsp70 and Hsp90 families, have been assessed as potential anti-trypanosomal drug targets [252][253][254].…”

Section: Heat Shock Protein 70 and 90mentioning

confidence: 99%

“…The T. brucei cytosolic Hsp70 complement consists of three paralogues, namely TbHsp70 and TbHsp70.c, which are heat inducible, and TbHsp70.4, which is non-inducible [246,253,254]. TbHsp70 and TbHsp70.4 were susceptible to malonganenone and nuttingin compounds, which modulated their substrate-binding capabilities, and were trypanocidal [255].…”

Section: Trypanosoma Brucei Hsp70mentioning

confidence: 99%

“…TbHsp70.c possesses a divergent linker region, and substitutions at otherwise highly conserved amino acid residues within the substrate-binding pocket [256]. Furthermore, TbHsp70.c lacks the EEVD motif, which is essential for interacting with TPR domain-containing co-chaperones, such as the stress-inducible phosphoprotein 1 (STI1) [250,254]. STI1 serves as a regulator of substrate channeling between Hsp70 and Hsp90, and TbHsp70.c does not interact with T. brucei STI1 [256,257].…”

Section: Trypanosoma Brucei Hsp70mentioning

confidence: 99%

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Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies

Jamabo,

Mahlalela,

Edkins

et al. 2023

IJMS

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Human African trypanosomiasis is a neglected tropical disease caused by the extracellular protozoan parasite Trypanosoma brucei, and targeted for eradication by 2030. The COVID-19 pandemic contributed to the lengthening of the proposed time frame for eliminating human African trypanosomiasis as control programs were interrupted. Armed with extensive antigenic variation and the depletion of the B cell population during an infectious cycle, attempts to develop a vaccine have remained unachievable. With the absence of a vaccine, control of the disease has relied heavily on intensive screening measures and the use of drugs. The chemotherapeutics previously available for disease management were plagued by issues such as toxicity, resistance, and difficulty in administration. The approval of the latest and first oral drug, fexinidazole, is a major chemotherapeutic achievement for the treatment of human African trypanosomiasis in the past few decades. Timely and accurate diagnosis is essential for effective treatment, while poor compliance and resistance remain outstanding challenges. Drug discovery is on-going, and herein we review the recent advances in anti-trypanosomal drug discovery, including novel potential drug targets. The numerous challenges associated with disease eradication will also be addressed.

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Section: Heat Shock Protein 70 and 90mentioning

confidence: 99%

Section: Trypanosoma Brucei Hsp70mentioning

confidence: 99%

Section: Trypanosoma Brucei Hsp70mentioning

confidence: 99%

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Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies

Jamabo,

Mahlalela,

Edkins

et al. 2023

IJMS

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Quercetin as a Promising Antiprotozoan Phytochemical: Current Knowledge and Future Research Avenues

Memariani,

Ghasemian

2024

BioMed Research International

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Despite tremendous advances in the prevention and treatment of infectious diseases, only few antiparasitic drugs have been developed to date. Protozoan infections such as malaria, leishmaniasis, and trypanosomiasis continue to exact an enormous toll on public health worldwide, underscoring the need to discover novel antiprotozoan drugs. Recently, there has been an explosion of research into the antiprotozoan properties of quercetin, one of the most abundant flavonoids in the human diet. In this review, we tried to consolidate the current knowledge on the antiprotozoal effects of quercetin and to provide the most fruitful avenues for future research. Quercetin exerts potent antiprotozoan activity against a broad spectrum of pathogens such as Leishmania spp., Trypanosoma spp., Plasmodium spp., Cryptosporidium spp., Trichomonas spp., and Toxoplasma gondii. In addition to its immunomodulatory roles, quercetin disrupts mitochondrial function, induces apoptotic/necrotic cell death, impairs iron uptake, inhibits multiple enzymes involved in fatty acid synthesis and the glycolytic pathways, suppresses the activity of DNA topoisomerases, and downregulates the expression of various heat shock proteins in these pathogens. In vivo studies also show that quercetin is effective in reducing parasitic loads, histopathological damage, and mortality in animals. Future research should focus on designing effective drug delivery systems to increase the oral bioavailability of quercetin. Incorporating quercetin into various nanocarrier systems would be a promising approach to manage localized cutaneous infections. Nevertheless, clinical trials are needed to validate the efficacy of quercetin in treating various protozoan infections.

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Bioactivity of Natural Polyphenols as Antiparasitic Agents and their Biochemical Targets

Soto‐Sanchez

2022

MRMC

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Background: Leishmaniasis and trypanosomiasis are diseases that affect public health worldwide due to their high incidence, morbidity, and mortality. Available treatments are costly, prolonged, and toxic, not to mention the problem of parasite resistance. The development of alternative treatments is justified and polyphenols show promising activity. Objective: The main aim of this mini-review was to analyze the most promising phenolic compounds with reported antileishmanial and antitrypanosomal activity as well as their mechanisms of action. Results: We found that the mode of action of these natural compounds mainly lignans, neolignans, and flavonoids depends on the organism they act on and includes, macrophage activation, induction of morphological changes such as chromatin Conclusion: Although the specific molecular targets, bioavailability, route of administration, and dosages of some of these natural compounds need to be determined, polyphenols and their combinations represent a very promising and safe strategy to be considered for use against Leishmania spp and Trypanosoma spp. In addition, these compounds may provide a scaffold for developing new, more potent, and more selective antiprotozoal agents.

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Characterization of an Atypical Trypanosoma brucei Hsp70 Demonstrates Its Cytosolic-Nuclear Localization and Modulation by Quercetin and Methylene Blue

Cited by 3 publications

References 47 publications

Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies

Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies

Quercetin as a Promising Antiprotozoan Phytochemical: Current Knowledge and Future Research Avenues

Bioactivity of Natural Polyphenols as Antiparasitic Agents and their Biochemical Targets

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