Investigation of thiazolyl-benzothiophenamides as potential agents for African sleeping sickness.
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ABSTRACT:
SUBMITTER: Brown RW
PROVIDER: S-EPMC8126881 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human African trypanosomiasis (HAT), also known as African sleeping sickness, is caused by parasitic protozoa of the genus Trypanosoma. As the disease progresses, the parasites cross the blood brain barrier and are lethal for the patients if the disease is left untreated. Current therapies suffer from several drawbacks due to e.g. toxicity of the respective compounds or resistance to approved antitrypanosomal drugs. In this review, the different strategies of drug development against HAT are considered, namely the target-based approach, the phenotypic high throughput screening and the drug repurposing strategy. The most promising compounds emerging from these approaches entering an in vivo evaluation are mentioned herein. Of note, it may turn out to be difficult to confirm in vitro activity in an animal model of infection; however, possible reasons for the missing efficacy in unsuccessful in vivo studies are discussed.
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Project description:Gambiense human African trypanosomiasis (gHAT, sleeping sickness) is one of several neglected tropical diseases (NTDs) where there is evidence of asymptomatic human infection but there is uncertainty of the role it plays in transmission and maintenance. To explore possible consequences of asymptomatic infections, particularly in the context of elimination of transmission-a goal set to be achieved by 2030-we propose a novel dynamic transmission model to account for the asymptomatic population. This extends an established framework, basing infection progression on a number of experimental and observation gHAT studies. Asymptomatic gHAT infections include those in people with blood-dwelling trypanosomes, but no discernible symptoms, or those with parasites only detectable in skin. Given current protocols, asymptomatic infection with blood parasites may be diagnosed and treated, based on observable parasitaemia, in contrast to many other diseases for which treatment (and/or diagnosis) may be based on symptomatic infection. We construct a model in which exposed people can either progress to either asymptomatic skin-only parasite infection, which would not be diagnosed through active screening algorithms, or blood-parasite infection, which is likely to be diagnosed if tested. We add extra parameters to the baseline model including different self-cure, recovery, transmission and detection rates for skin-only or blood infections. Performing sensitivity analysis suggests all the new parameters introduced in the asymptomatic model can impact the infection dynamics substantially. Among them, the proportion of exposures resulting in initial skin or blood infection appears the most influential parameter. For some plausible parameterisations, an initial fall in infection prevalence due to interventions could subsequently stagnate even under continued screening due to the formation of a new, lower endemic equilibrium. Excluding this scenario, our results still highlight the possibility for asymptomatic infection to slow down progress towards elimination of transmission. Location-specific model fitting will be needed to determine if and where this could pose a threat.
| S-EPMC8459990 | biostudies-literature
Project description:The tsetse fly-transmitted protozoan parasite Trypanosoma brucei is the causative agent of human African sleeping sickness and the cattle disease Nagana. The bloodstream form of the parasite uses a dense cell-surface coat of variant surface glycoprotein to escape the innate and adaptive immune responses of the mammalian host and a highly glycosylated transferrin receptor to take up host transferrin, an essential growth factor. These glycoproteins, as well as other flagellar pocket, endosomal, and lysosomal glycoproteins, are known to contain galactose. The parasite is unable to take up galactose, suggesting that it may depend on the action of UDP-glucose 4'-epimerase for the conversion of UDP-Glc to UDP-Gal and subsequent incorporation of galactose into glycoconjugates via UDP-Gal-dependent galactosyltransferases. In this paper, we describe the cloning of T. brucei galE, encoding T. brucei UDP-Glc-4'-epimerase, and functional characterization by complementation of a galE-deficient Escherichia coli mutant and enzymatic assay of recombinant protein. A tetracycline-inducible conditional galE null mutant of T. brucei was created using a transgenic parasite expressing the TETR tetracycline repressor protein gene. Withdrawal of tetracycline led to a cessation of cell division and substantial cell death, demonstrating that galactose metabolism in T. brucei proceeds via UDP-Glc-4'-epimerase and is essential for parasite growth. After several days without tetracycline, cultures spontaneously recovered. These cells were shown to have undergone a genetic rearrangement that deleted the TETR gene. The results show that enzymes and transporters involved in galactose metabolism may be considered as potential therapeutic targets against African trypanosomiasis.
| S-EPMC122871 | biostudies-literature
Project description:The protozoan Trypanosoma brucei causes African Trypanosomiasis or sleeping sickness in humans, which can be lethal if untreated. Most available pharmacological treatments for the disease have severe side-effects. The purpose of this analysis was to detect novel protein-protein interactions (PPIs), vital for the parasite, which could lead to the development of drugs against this disease to block the specific interactions. In this work, the Domain Fusion Analysis (Rosetta Stone method) was used to identify novel PPIs, by comparing T. brucei to 19 organisms covering all major lineages of the tree of life. Overall, 49 possible protein-protein interactions were detected, and classified based on (a) statistical significance (BLAST e-value, domain length etc.), (b) their involvement in crucial metabolic pathways, and (c) their evolutionary history, particularly focusing on whether a protein pair is split in T. brucei and fused in the human host. We also evaluated fusion events including hypothetical proteins, and suggest a possible molecular function or involvement in a certain biological process. This work has produced valuable results which could be further studied through structural biology or other experimental approaches so as to validate the protein-protein interactions proposed here. The evolutionary analysis of the proteins involved showed that, gene fusion or gene fission events can happen in all organisms, while some protein domains are more prone to fusion and fission events and present complex evolutionary patterns.
| S-EPMC3714255 | biostudies-literature
Project description:The protozoan parasite Trypanosoma brucei is the causative agent of human African sleeping sickness and related animal diseases, and it has over 170 predicted protein kinases. Protein phosphorylation is a key regulatory mechanism for cellular function that, thus far, has been studied in T.brucei principally through putative kinase mRNA knockdown and observation of the resulting phenotype. However, despite the relatively large kinome of this organism and the demonstrated essentiality of several T. brucei kinases, very few specific phosphorylation sites have been determined in this organism. Using a gel-free, phosphopeptide enrichment-based proteomics approach we performed the first large scale phosphorylation site analyses for T.brucei. Serine, threonine, and tyrosine phosphorylation sites were determined for a cytosolic protein fraction of the bloodstream form of the parasite, resulting in the identification of 491 phosphoproteins based on the identification of 852 unique phosphopeptides and 1204 phosphorylation sites. The phosphoproteins detected in this study are predicted from their genome annotations to participate in a wide variety of biological processes, including signal transduction, processing of DNA and RNA, protein synthesis, and degradation and to a minor extent in metabolic pathways. The analysis of phosphopeptides and phosphorylation sites was facilitated by in-house developed software, and this automated approach was validated by manual annotation of spectra of the kinase subset of proteins. Analysis of the cytosolic bloodstream form T. brucei kinome revealed the presence of 44 phosphorylated protein kinases in our data set that could be classified into the major eukaryotic protein kinase groups by applying a multilevel hidden Markov model library of the kinase catalytic domain. Identification of the kinase phosphorylation sites showed conserved phosphorylation sequence motifs in several kinase activation segments, supporting the view that phosphorylation-based signaling is a general and fundamental regulatory process that extends to this highly divergent lower eukaryote.
| S-EPMC2716717 | biostudies-literature
Project description:It has been suggested that compounds affecting glycosylphosphatidylinositol (GPI) biosynthesis in bloodstream form Trypanosoma brucei should be trypanocidal. We describe cell-permeable analogues of a GPI intermediate that are toxic to this parasite but not to human cells. These analogues are metabolized by the T. brucei GPI pathway, but not by the human pathway. Closely related nonmetabolizable analogues have no trypanocidal activity. This represents the first direct chemical validation of the GPI biosynthetic pathway as a drug target against African human sleeping sickness. The results should stimulate further inhibitor design and synthesis and encourage the search for inhibitors in natural product and synthetic compound libraries.
| S-EPMC533043 | biostudies-literature
Project description:Pteridine reductase (PTR1) is a target for drug development against Trypanosoma and Leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. We adopted a structure-based approach to the design of novel PTR1 inhibitors based on three molecular scaffolds. A series of compounds, most newly synthesized, were identified as inhibitors with PTR1-species specific properties explained by structural differences between the T. brucei and L. major enzymes. The most potent inhibitors target T. brucei PTR1, and two compounds displayed antiparasite activity against the bloodstream form of the parasite. PTR1 contributes to antifolate drug resistance by providing a molecular bypass of dihydrofolate reductase (DHFR) inhibition. Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic effect was observed for one particular combination highlighting the potential of such an approach for treatment of African sleeping sickness.
| S-EPMC2804273 | biostudies-literature
Project description:Sleeping sickness is a fatal disease caused by Trypanosoma brucei, a unicellular parasite that lives in the bloodstream and interstitial spaces of peripheral tissues and the brain. Patients have altered sleep/wake cycles, body temperature, and endocrine profiles, but the underlying causes are unknown. Here, we show that the robust circadian rhythms of mice become phase advanced upon infection, with abnormal activity occurring during the rest phase. This advanced phase is caused by shortening of the circadian period both at the behavioral level as well as at the tissue and cell level. Period shortening is T. brucei specific and independent of the host immune response, as co-culturing parasites with explants or fibroblasts also shortens the clock period, whereas malaria infection does not. We propose that T. brucei causes an advanced circadian rhythm disorder, previously associated only with mutations in clock genes, which leads to changes in the timing of sleep.
| S-EPMC5754353 | biostudies-literature
Project description:Human African trypanosomiasis (HAT) is a disease caused by infection with the parasite Trypanosoma brucei gambiense or T. b. rhodesiense. It is transmitted to humans via the tsetse fly. Approximately 70 million people worldwide were at risk of infection in 1995, and approximately 20,000 people across Africa are infected with HAT. The objective of this review was to identify existing economic evaluations in order to summarise cost-effective interventions to reduce, control, or eliminate the burden of HAT. The studies included in the review were compared and critically appraised in order to determine if there were existing standardised methods that could be used for economic evaluation of HAT interventions or if innovative methodological approaches are warranted. A search strategy was developed using keywords and was implemented in January 2014 in several databases. The search returned a total of 2,283 articles. After two levels of screening, a total of seven economic evaluations were included and underwent critical appraisal using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist 6: Economic Evaluations. Results from the existing studies focused on the cost-effectiveness of interventions for the control and reduction of disease transmission. Modelling was a common method to forecast long-term results, and publications focused on interventions by category, such as case detection, diagnostics, drug treatments, and vector control. Most interventions were considered cost-effective based on the thresholds described; however, the current treatment, nifurtomix-eflornithine combination therapy (NECT), has not been evaluated for cost-effectiveness, and considerations for cost-effective strategies for elimination have yet to be completed. Overall, the current evidence highlights the main components that play a role in control; however, economic evaluations of HAT elimination strategies are needed to assist national decision makers, stakeholders, and key funders. These analyses would be of use, as HAT is currently being prioritized as a neglected tropical disease (NTD) to reach elimination by 2020.
| S-EPMC4318581 | biostudies-other
Project description:Neglected tropical disease drug discovery requires application of pragmatic and efficient methods for development of new therapeutic agents. In this report, we describe our target repurposing efforts for the essential phosphodiesterase (PDE) enzymes TbrPDEB1 and TbrPDEB2 of Trypanosoma brucei , the causative agent for human African trypanosomiasis (HAT). We describe protein expression and purification, assay development, and benchmark screening of a collection of 20 established human PDE inhibitors. We disclose that the human PDE4 inhibitor piclamilast, and some of its analogues, show modest inhibition of TbrPDEB1 and B2 and quickly kill the bloodstream form of the subspecies T. brucei brucei . We also report the development of a homology model of TbrPDEB1 that is useful for understanding the compound-enzyme interactions and for comparing the parasitic and human enzymes. Our profiling and early medicinal chemistry results strongly suggest that human PDE4 chemotypes represent a better starting point for optimization of TbrPDEB inhibitors than those that target any other human PDEs.
| S-EPMC3228873 | biostudies-literature