Human African Trypanosomiasis (HAT) is an endemic protozoan disease widespread in the sub-Saharan region that is caused by T. b. gambiense and T. b. rhodesiense. The development of molecules targeting rhodesain, the main cysteine protease of T. b. rhodesiense, has led to a panel of inhibitors endowed with micro/sub-micromolar activity towards the protozoa. However, whilst impressive binding affinity against rhodesain has been observed, the limited selectivity towards the target still remains a hard challenge for the development of antitrypanosomal agents. In this paper, we report the synthesis, biological evaluation, as well as docking studies of a series of reduced peptide bond pseudopeptide Michael acceptors (SPR10-SPR19) as potential anti-HAT agents. The new molecules show Ki values in the low-micro/sub-micromolar range against rhodesain, coupled with k2nd values between 1314 and 6950 M-1 min-1. With a few exceptions, an appreciable selectivity over human cathepsin L was observed. In in vitro assays against T. b. brucei cultures, SPR16 and SPR18 exhibited single-digit micromolar activity against the protozoa, comparable to those reported for very potent rhodesain inhibitors, while no significant cytotoxicity up to 70 µM towards mammalian cells was observed. The discrepancy between rhodesain inhibition and the antitrypanosomal effect could suggest additional mechanisms of action. The biological characterization of peptide inhibitor SPR34 highlights the essential role played by the reduced bond for the antitrypanosomal effect. Overall, this series of molecules could represent the starting point for further investigations of reduced peptide bond-containing analogs as potential anti-HAT agents.

African trypanosomiasis is a parasitic disease affecting 5000 humans and millions of livestock animals in sub-Saharan Africa every year. Current treatments are limited, difficult to administer and often toxic causing long term injury or death in many patients. Trypanosome alternative oxidase is a parasite specific enzyme whose inhibition by the natural product ascofuranone (AF) has been shown to be curative in murine models. Until now synthetic methods to AF analogues have been limited, this has restricted both understanding of the key structural features required for binding and also how this chemotype could be developed to an effective therapeutic agent. The development of 3 amenable novel synthetic routes to ascofuranone-like compounds is described. The SAR generated around the AF chemotype is reported with correlation to the inhibition of T. b. brucei growth and corresponding selectivity in cytotoxic assessment in mammalian HepG2 cell lines. These methods allow access to greater synthetic diversification and have enabled the synthesis of compounds that have and will continue to facilitate further optimisation of the AF chemotype into a drug-like lead.

The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.

Control operations targeting Animal African Trypanosomiasis and its primary vector, the tsetse, were covering approximately 128,000 km2 of Africa in 2001, which is a mere 1.3% of the tsetse infested area. Although extensive trypanosomiasis and tsetse (T&T) control operations have been running since the beginning of the 20th century, Animal African Trypanosomiasis is still a major constraint of livestock production in sub-Saharan Africa.

In 1994, combined active and passive screening reported 1469 cases from the historic Gambian Human African Trypanosomiasis (gHAT) foci of West Nile, Uganda. Since 2011 systematic active screening has stopped and there has been reliance on passive screening. During 2014, passive screening alone detected just nine cases. In the same year a tsetse control intervention was expanded to cover the main gHAT foci in West Nile to curtail transmission of gHAT contributing to the elimination of gHAT as a public health problem in the area. It is known that sole reliance on passive screening is slow to detect cases and can underestimate the actual true number. We therefore undertook an active screening programme designed to test the efficacy of these interventions against gHAT transmission and clarify disease status. Screening was conducted in 28 randomly selected villages throughout the study area, aiming to sample all residents. Whole blood from 10,963 participants was analysed using CATT and 97 CATT suspects (0.9%) were evaluated with microscopy and trypanolysis. No confirmed cases were found providing evidence that the gHAT prevention programmes in West Nile have been effective. Results confirm gHAT prevalence in the study area of West Nile is below the elimination threshold (1 new case / 10,000 population), making elimination on course across this study area if status is maintained. The findings of this study can be used to guide future HAT and tsetse management in other gHAT foci, where reduced caseloads necessitate a shift from active to passive screening.

Several modeling studies have been undertaken to assess the feasibility of the WHO goal of eliminating gambiense human African trypanosomiasis (g-HAT) by 2030. However, these studies have generally overlooked the effect of vector migration on disease transmission and control. Here, we evaluated the impact of vector migration on the feasibility of interrupting transmission in different g-HAT foci.

No abstract available

Human African trypanosomiasis or sleeping sickness, caused by the parasite Trypanosoma brucei, leads to neuroinflammation and characteristic sleep/wake alterations. The relationship between the onset of these alterations and the development of neuroinflammation is of high translational relevance, but remains unclear. This study investigates the expression of interferon (IFN)-γ and IFN-inducible chemokine genes in the brain, and the levels of CXCL10 in the serum and cerebrospinal fluid prior to and during the encephalitic stage of trypanosome infection, and correlates these with sleep/wake changes in a rat model of the disease.

The World Health Organization (WHO) has set the goal of gambiense-Human African trypanosomiasis (HAT) elimination as a public health problem for 2020 and interruption of transmission in humans for 2030. In this context, it is crucial to monitor progress towards these targets using accurate tools to assess the level of transmission in a given area. The aim of this study was to investigate the relevance of the immune trypanolysis test (TL) as a population-based bioassay to evaluate Trypanosoma brucei gambiense transmission in various epidemiological contexts. Significant correlations were observed between HAT endemicity levels and the percentage of TL-positive individuals in the population. TL therefore appears to be a suitable population-based biomarker of the intensity of transmission. In addition to being used as a tool to assess the HAT status at an individual level, assessing the proportion of TL positive individuals in the population appears as a promising and easy alternative to monitor the elimination of gambiense HAT in a given area.

Human African trypanosomiasis (HAT) is an important public health problem in sub-Saharan Africa, affecting hundreds of thousands of individuals. An urgent need exists for the discovery and development of new, safe, and effective drugs to treat HAT, as existing therapies suffer from poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. We have discovered and optimized a novel class of small-molecule boron-containing compounds, benzoxaboroles, to identify SCYX-7158 as an effective, safe and orally active treatment for HAT.

Human African Trypanosomiasis (HAT) is a parasitic disease originating in sub-Saharan Africa. There is limited information about the changes in the blood brain barrier (BBB) during this infection. This study is the first to apply diffusion weighted ASL (DWASL) to examine changes in BBB impairment. No significant changes in water exchange across the BBB were found during the infection, even when a loss of barrier integrity was seen using Contrast Enhanced MRI (Gd-DTPA) during the late stage of the disease. Furthermore, using multiple boli ASL (mbASL), changes in cerebral blood flow (CBF) were found during the course of infection. Overall, this study highlights the need for further study of the BBB during HAT infection to understand the complex mechanisms behind impairment.

Human African trypanosomiasis is a parasitic disease caused by trypanosomes among which Trypanosoma brucei gambiense is responsible for a chronic form (gHAT) in West and Central Africa. Its elimination as a public health problem (EPHP) was targeted for 2020. Côte d'Ivoire was one of the first countries to be validated by WHO in 2020 and this was particularly challenging as the country still reported around a hundred cases a year in the early 2000s. This article describes the strategies implemented including a mathematical model to evaluate the reporting results and infer progress towards sustainable elimination.

Strategies to detect Human African Trypanosomiasis (HAT) cases rely on serological screening of populations exposed to trypanosomes. In Guinea, mass medical screening surveys performed with the Card Agglutination Test for Trypanosomiasis have been progressively replaced by door-to-door approaches using Rapid Diagnostic Tests (RDTs) since 2016. However, RDTs availability represents a major concern and medical teams must often adapt, even in the absence of prior RDT performance evaluation. For the last 5 years, the Guinean HAT National Control Program had to combine three different RDTs according to their availability and price: the SD Bioline HAT (not available anymore), the HAT Sero-K-SeT (most expensive), and recently the Abbott Bioline HAT 2.0 (limited field evaluation). Here, we assess the performance of these RDTs, alone or in different combinations, through the analysis of both prospective and retrospective data. A parallel assessment showed a higher positivity rate of Abbott Bioline HAT 2.0 (6.0%, n = 2,250) as compared to HAT Sero-K-SeT (1.9%), with a combined positive predictive value (PPV) of 20.0%. However, an evaluation of Abbott Bioline HAT 2.0 alone revealed a low PPV of 3.9% (n = 6,930) which was surpassed when using Abbott Bioline HAT 2.0 in first line and HAT Sero-K-SeT as a secondary test before confirmation, with a combined PPV reaching 44.4%. A retrospective evaluation of all 3 RDTs was then conducted on 189 plasma samples from the HAT-NCP biobank, confirming the higher sensitivity (94.0% [85.6-97.7%]) and lower specificity (83.6% [76.0-89.1%]) of Abbott Bioline HAT 2.0 as compared to SD Bioline HAT (Se 64.2% [52.2-74.6%]-Sp 98.4% [94.2-99.5%]) and HAT Sero-K-SeT (Se 88.1% [78.2-93.8%]-Sp 98.4% [94.2-99.5%]). A comparison of Abbott Bioline HAT 2.0 and malaria-RDT positivity rates on 479 subjects living in HAT-free malaria-endemic areas further revealed that a significantly higher proportion of subjects positive in Abbott Bioline HAT 2.0 were also positive in malaria-RDT, suggesting a possible cross-reaction of Abbott Bioline HAT 2.0 with malaria-related biological factors in about 10% of malaria cases. This would explain, at least in part, the limited specificity of Abbott Bioline HAT 2.0. Overall, Abbott Bioline HAT 2.0 seems suitable as first line RDT in combination with a second HAT RDT to prevent confirmatory lab overload and loss of suspects during referral for confirmation. A state-of-the-art prospective comparative study is further required for comparing all current and future HAT RDTs to propose an optimal combination of RDTs for door-to-door active screening.

African animal trypanosomiasis is an economically significant disease that affects the livestock industry in Nigeria. It is caused by several parasites of the genus Trypanosoma. National estimates of the disease prevalence in livestock and tsetse flies are lacking, therefore a systematic review and meta-analysis were performed to understand the trend of the disease prevalence over the years.

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.

Spliced Leader (SL) trypanosome RNA is detectable only in the presence of live trypanosomes, is abundant and the Trypanozoon subgenus has a unique sequence. As previously shown in blood from Guinean human African trypanosomiasis (HAT) patients, SL-RNA is an accurate target for diagnosis. Detection of SL-RNA in the cerebrospinal fluid (CSF) has never been attempted. In a large group of Congolese gambiense HAT patients, the present study aims i) to confirm the sensitivity of SL-RNA detection in the blood and; ii) to assess the diagnostic performance of SL-RNA compared to trypanosome detection in CSF.

Eflornithine is a recommended treatment against the otherwise fatal parasitic disease late stage human African trypanosomiasis (HAT), also known as Gambian sleeping sickness. It is administered repeatedly as a racemic mixture intravenously (IV) together with oral nifurtimox. Racemic eflornithine has been investigated in clinical trials for oral dosing. However, due to low systemic exposures at a maximum tolerated oral dose, the drug is continued to be administered IV. The eflornithine enantiomers, d- and l-eflornithine, have different affinities to the target enzyme ornithine decarboxylase, suggesting that the pharmacodynamics of the enantiomers may differ. The aim of this study was to develop a method for isolation of d- and l-eflornithine from a racemic mixture. Several chiral stationary phases (CSPs) were evaluated for enantioselectivity using supercritical fluid chromatography (SFC) or high-performance liquid chromatography (HPLC). None of the tested CSPs rendered separation of the enantiomers in SFC mode. Separation of the enantiomers with SFC on the CSP Chiralpak IG was only achieved on an analytical scale after derivatization with ortho-phthalaldehyde (OPA). This was the first reported enantioselective SFC method for an eflornithine derivate. However, due to poor stability, the eflornithine-OPA derivates degraded and no chemically pure enantiomers were obtained. The CSP that showed enantioselectivity in HPLC mode was Chirobiotic R, which resulted in a successful isolation on a semipreparative milligram scale. The isolated eflornithine enantiomers will be tested in nonclinical in vitro and in vivo studies to support and assess the feasibility of a future clinical program with an oral HAT treatment.

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a parasitic tropical disease. It progresses from the first, haemolymphatic stage to a neurological second stage due to invasion of parasites into the central nervous system (CNS). As treatment depends on the stage of disease, there is a critical need for tools that efficiently discriminate the two stages of HAT. We hypothesized that markers of brain damage discovered by proteomic strategies and inflammation-related proteins could individually or in combination indicate the CNS invasion by the parasite.

Human African trypanosomiasis (HAT) is a neglected tropical disease still endemic in the Republic of Congo. Despite the continuous detection of HAT cases in the country, there is still not enough data on trypanosome infections in tsetse flies, trypanosome species and tsetse flies' species distribution in endemic foci. The present study was intended to fill this gap and improve understanding of trypanosome circulation in three active foci in the centre and south of Congo.

We designed and synthesized a series of symmetric bis-6-amidino-benzothiazole derivatives with aliphatic central units and evaluated their efficacy against bloodstream forms of the African trypanosome Trypanosoma brucei. Of these, a dicationic benzothiazole compound (9a) exhibited sub-nanomolar in vitro potency with remarkable selectivity over mammalian cells (>26,000-fold). Unsubstituted 5-amidine groups and a cyclohexyl spacer were the crucial determinants of trypanocidal activity. In all cases, mice treated with a single dose of 20 mg kg-1 were cured of stage 1 trypanosomiasis. The compound displayed a favorable in vitro ADME profile, with the exception of low membrane permeability. However, we found evidence that uptake by T. brucei is mediated by endocytosis, a process that results in lysosomal sequestration. The compound was also active in low nanomolar concentrations against cultured asexual forms of the malaria parasite Plasmodium falciparum. Therefore, 9a has exquisite cross-species efficacy and represents a lead compound with considerable therapeutic potential.