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Kinetoplastids are a group of flagellated protozoans including medically important parasites of the genus Trypanosoma and Leishmania. The corresponding diseases have afflicted humans for centuries. In an effort to combat kinetoplastid infections, a set of 21 chalcones was synthesized and evaluated for their in vitro anti-protozoal efficacy against Trypanosoma brucei, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania infantum. To ensure safety, these compounds underwent a selectivity evaluation by assessing toxicity against a human lung fibroblast cell line. Compound K4 exhibited remarkable and selective trypanocidal activity against T. b. brucei with IC50 value of 0.31 ± 0.27 µM and T. b. rhodesiense with IC50 value of 0.96 ± 0.86 µM. Compound K9 also showed significant trypanocidal activity against T. b. brucei (IC50: 0.45 ± 0.14 µM) and T. b. rhodesiense (IC50: 0.93 ± 0.51 µM). In both compounds, electron withdrawing groups are appended to the styrenyl moiety. [ABSTRACT FROM AUTHOR]

Following the medical breakthroughs of Pasteur and Koch after 1880, the use of simians became pivotal to laboratory research to develop vaccines and cultivate microbes through the technique of serial passage. These innovations fueled research on multiple diseases and unleashed a demand for simians, which died easily in captivity. European and American colonial expansion facilitated a burgeoning market for laboratory animals that intensified hunting for live animals. This demand created novel opportunities for disease transfers and viral recombinations as simians of different species were confined in precarious settings. As laboratories moved into the colonies for research into a variety of diseases, notably syphilis, sleeping sickness, and malaria, the simian market was intensified. While researchers expected that colonial laboratories offered more natural environments than their metropolitan affiliates, amassing apes, people, microbes, and insects at close quarters instead created unnatural conditions that may have facilitated the spread of undetectable diseases. [ABSTRACT FROM AUTHOR]

This overview initially describes insect immune reactions and then brings together present knowledge of the interactions of vector insects with their invading parasites and pathogens. It is a way of introducing this Special Issue with subsequent papers presenting the latest details of these interactions in each particular group of vectors. Hopefully, this paper will fill a void in the literature since brief descriptions of vector immunity have now been brought together in one publication and could form a starting point for those interested and new to this important area. Descriptions are given on the immune reactions of mosquitoes, blackflies, sandflies, tsetse flies, lice, fleas and triatomine bugs. Cellular and humoral defences are described separately but emphasis is made on the co-operation of these processes in the completed immune response. The paper also emphasises the need for great care in extracting haemocytes for subsequent study as appreciation of their fragile nature is often overlooked with the non-sterile media, smearing techniques and excessive centrifugation sometimes used. The potential vital role of eicosanoids in the instigation of many of the immune reactions described is also discussed. Finally, the priming of the immune system, mainly in mosquitoes, is considered and one possible mechanism is presented. [ABSTRACT FROM AUTHOR]

Human African Trypanosomiasis is a serious public health concern, and new chemical therapeutic agents need to be developed to combat this disease. Rhodesain (RhD) inhibitors have shown promising results in medicinal chemistry, specifically against Trypanosoma brucei. These inhibitors target the cysteine protease RhD, which is essential for the survival of T. brucei. However, as the pharmaceutical industry lacks interest in these inhibitors, the development of drugs based on them is challenging. In this review, we showed the impact of RhD inhibitors on medicinal chemistry in the past 10 years (2013–2022), particularly against T. brucei, showing interesting RhD-based inhibitors, including peptidomimetic inhibitors such as Michael acceptors, cyanide groups, 3-bromoisoxazole, benzodiazepine, among others, as well as non-peptidyl inhibitors. Peptidomimetic inhibitors (5–7, 9–15, and 17) exhibited the highest potency with respect to dissociation constant (Ki) values for rhodesain, demonstrating promising activity against T. brucei targeting rhodesain. Thus, we explored recent advancements and perspectives in the context of RhD for potential treatments in sleeping sickness, highlighting its relevance in drug discovery applications. [ABSTRACT FROM AUTHOR]

Apolipoprotein-L1 (APOL1) is a membrane-interacting protein induced by inflammation, which confers human resistance to infection by African trypanosomes. APOL1 kills Trypanosoma brucei through induction of apoptotic-like parasite death, but two T. brucei clones acquired resistance to APOL1, allowing them to cause sleeping sickness. An APOL1 C-terminal sequence alteration, such as occurs in natural West African variants G1 and G2, restored human resistance to these clones. However, APOL1 unfolding induced by G1 or G2 mutations enhances protein hydrophobicity, resulting in kidney podocyte dysfunctions affecting renal filtration. The mechanism involved in these dysfunctions is debated. The ability of APOL1 to generate ion pores in trypanosome intracellular membranes or in synthetic membranes was provided as an explanation. However, transmembrane insertion of APOL1 strictly depends on acidic conditions, and podocyte cytopathology mainly results from secreted APOL1 activity on the plasma membrane, which occurs under non-acidic conditions. In this review, I argue that besides inactivation of APOL3 functions in membrane dynamics (fission and fusion), APOL1 variants induce inflammation-linked podocyte toxicity not through pore formation, but through plasma membrane disturbance resulting from increased interaction with cholesterol, which enhances cation channels activity. A natural mutation in the membrane-interacting domain (N264K) abrogates variant APOL1 toxicity at the expense of slightly increased sensitivity to trypanosomes, further illustrating the continuous mutual adaptation between host and parasite.

The functions of human Apolipoproteins L (APOLs) are poorly understood, but involve diverse activities like lysis of bloodstream trypanosomes and intracellular bacteria, modulation of viral infection and induction of apoptosis, autophagy, and chronic kidney disease. Based on recent work, I propose that the basic function of APOLs is the control of membrane dynamics, at least in the Golgi and mitochondrion. Together with neuronal calcium sensor-1 (NCS1) and calneuron-1 (CALN1), APOL3 controls the activity of phosphatidylinositol-4-kinase-IIIB (PI4KB), involved in both Golgi and mitochondrion membrane fssion. Whereas secreted APOL1 induces African trypanosome lysis through membrane permeabilization of the parasite mitochondrion, intracellular APOL1 conditions non-muscular myosin-2A (NM2A)-mediated transfer of PI4KB and APOL3 from the Golgi to the mitochondrion under conditions interfering with PI4KB-APOL3 interaction, such as APOL1 C-terminal variant expression or virus-induced infammatory signalling. APOL3 controls mitophagy through complementary interactions with the membrane fssion factor PI4KB and the membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). In mice, the basic APOL1 and APOL3 activities could be exerted by mAPOL9 and mAPOL8, respectively. Perspectives regarding the mechanism and treatment of APOL1-related kidney disease are discussed, as well as speculations on additional APOLs functions, such as APOL6 involvement in adipocyte membrane dynamics through interaction with myosin-10 (MYH10). [ABSTRACT FROM AUTHOR]

Suramin was the first drug developed using the approach of medicinal chemistry by the German Bayer company in the 1910s for the treatment of human African sleeping sickness caused by the two subspecies Trypanosoma brucei gambiense and Trypanosoma brucei rhodesienese. However, the drug was politically instrumentalized by the German government in the 1920s in an attempt to regain possession of its former African colonies lost after the First World War. For this reason, the formula of suramin was kept secret for more than 10 years. Eventually, the French pharmacist Ernest Fourneau uncovered the chemical structure of suramin by reverse engineering and published the formula of the drug in 1924. During the Nazi period, suramin became the subject of colonial revisionism, and the development of the drug was portrayed in books and films to promote national socialist propaganda. Ever since its discovery, suramin has also been tested for bioactivity against numerous other infections and diseases. However, sleeping sickness caused by Trypanosoma brucei rhodesiense is the only human disease for which treatment with suramin is currently approved. [ABSTRACT FROM AUTHOR]

Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world's poorest people: African trypanosomiasis or sleeping sickness, American trypanosomiasis or Chagas disease and different types of leishmaniasis. Different metabolic pathways have been targeted to find antitrypanosomatid drugs, including polyamine metabolism. Since their discovery, the naturally occurring polyamines, putrescine, spermidine and spermine, have been considered important metabolites involved in cell growth. With a complex metabolism involving biosynthesis, catabolism and interconversion, the synthesis of putrescine and spermidine was targeted by thousands of compounds in an effort to produce cell growth blockade in tumor and infectious processes with limited success. However, the discovery of eflornithine (DFMO) as a curative drug against sleeping sickness encouraged researchers to develop new molecules against these diseases. Polyamine synthesis inhibitors have also provided insight into the peculiarities of this pathway between the host and the parasite, and also among different trypanosomatid species, thus allowing the search for new specific chemical entities aimed to treat these diseases and leading to the investigation of target-based scaffolds. The main molecular targets include the enzymes involved in polyamine biosynthesis (ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine synthase), enzymes participating in their uptake from the environment, and the enzymes involved in the redox balance of the parasite. In this review, we summarize the research behind polyamine-based treatments, the current trends, and the main challenges in this field. [ABSTRACT FROM AUTHOR]

Abstract Background There have been many prediction studies for imported infectious diseases, employing air-travel volume or the importation risk (IR) index, which is the product of travel-volume and disease burden in the source countries, as major predictors. However, there is a lack of studies validating the predictability of the variables especially for infectious diseases that have rarely been reported. In this study, we analyzed the prediction performance of the IR index and air-travel volume to predict disease importation. Methods Rabies and African trypanosomiasis were used as target diseases. The list of rabies and African trypanosomiasis importation events, annual air-travel volume between two specific countries, and incidence of rabies and African trypanosomiasis in the source countries were obtained from various databases. Results Logistic regression analysis showed that IR index was significantly associated with rabies importation risk (p value

Human African Trypanosomiasis (HAT) is still endemic in the Republic of Congo. Although the incidence of cases has significantly decreased over years, the disease still persists in some active foci. Factors contributing to the maintenance of the disease such as the existence of an animal reservoir or population knowledge are still not well known. It is in this context that a study focusing on the knowledge and practices of the population with regard to HAT as well as on the prevalence of trypanosomes infecting animals was undertaken in three active HAT foci in the Republic of Congo. The study was performed using field surveys conducted from November 2019 to June 2021. Domestic animal blood was examined by microscopy and PCR to detect the presence of trypanosomes. A structured questionnaire was administered to the population to assess their knowledge and practices concerning HAT in these endemic foci. More than half of the animals examined were found to be infected with trypanosomes (51.22%). The main trypanosome species infecting animals were Trypanosoma congolense savannah (67.2%) and Trypanosoma brucei (s.l.) (32.8%). No trypanosomes infecting humans were detected. Concerning household surveys, more than half of the respondents (52.9%) were fully aware of the mode of transmission and symptoms of the disease. The majority of people preferred to wear clothes covering the whole body and to use locally made soap as repellents to protect themselves from tsetse fly bites. This study suggests frequent circulation of animal trypanosomes in domestic animals and the use of personal measures to protect against tsetse fly bites. Updating information on the HAT animal reservoir and population knowledge alongside regular monitoring of the tsetse fly populations and the use of traps to control tsetse flies are crucial to drive efforts towards the elimination of gHAT in the Republic of Congo.

Background: There have been many prediction studies for imported infectious diseases, employing air-travel volume or the importation risk (IR) index, which is the product of travel-volume and disease burden in the source countries, as major predictors. However, there is a lack of studies validating the predictability of the variables especially for infectious diseases that have rarely been reported. In this study, we analyzed the prediction performance of the IR index and air-travel volume to predict disease importation. Methods: Rabies and African trypanosomiasis were used as target diseases. The list of rabies and African trypanosomiasis importation events, annual air-travel volume between two specific countries, and incidence of rabies and African trypanosomiasis in the source countries were obtained from various databases. Results: Logistic regression analysis showed that IR index was significantly associated with rabies importation risk (p value < 0.001), but the association with African trypanosomiasis was not significant (p value = 0.923). The univariable logistic regression models showed reasonable prediction performance for rabies (area under curve for Receiver operating characteristic [AUC] = 0.734) but poor performance for African trypanosomiasis (AUC = 0.641). Conclusions: Our study found that the IR index cannot be generally applicable for predicting rare importation events. However, it showed the potential utility of the IR index by suggesting acceptable performance in rabies models. Further studies are recommended to explore the generalizability of the IR index's applicability and to propose disease-specific prediction models. [ABSTRACT FROM AUTHOR]

Human African Trypanosomiasis (HAT) is still endemic in the Republic of Congo. Although the incidence of cases has significantly decreased over years, the disease still persists in some active foci. Factors contributing to the maintenance of the disease such as the existence of an animal reservoir or population knowledge are still not well known. It is in this context that a study focusing on the knowledge and practices of the population with regard to HAT as well as on the prevalence of trypanosomes infecting animals was undertaken in three active HAT foci in the Republic of Congo. The study was performed using field surveys conducted from November 2019 to June 2021. Domestic animal blood was examined by microscopy and PCR to detect the presence of trypanosomes. A structured questionnaire was administered to the population to assess their knowledge and practices concerning HAT in these endemic foci. More than half of the animals examined were found to be infected with trypanosomes (51.22%). The main trypanosome species infecting animals were Trypanosoma congolense savannah (67.2%) and Trypanosoma brucei (s.l.) (32.8%). No trypanosomes infecting humans were detected. Concerning household surveys, more than half of the respondents (52.9%) were fully aware of the mode of transmission and symptoms of the disease. The majority of people preferred to wear clothes covering the whole body and to use locally made soap as repellents to protect themselves from tsetse fly bites. This study suggests frequent circulation of animal trypanosomes in domestic animals and the use of personal measures to protect against tsetse fly bites. Updating information on the HAT animal reservoir and population knowledge alongside regular monitoring of the tsetse fly populations and the use of traps to control tsetse flies are crucial to drive efforts towards the elimination of gHAT in the Republic of Congo. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Arunima Goswami, Tirthankar Koley, Madhan Vishal Rajan, Pathak Madhuri, Neelam Upadhyay, Uddipan Das, Manoj Kumar, Abdul Samath Ethayathulla, Gururao Hariprasad Department of Biophysics, All India Institute of Medical Sciences, New Delhi, 110029, IndiaCorrespondence: Gururao Hariprasad, Tel +91-11-26594240, Fax +91-11-26588663, Email dr.hariprasadg@gmail.comPurpose: Leishmaniasis, Chagas disease, and sleeping sickness are caused by protozoa Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, respectively. Platelet activating factor acetyl hydrolase (PAF-AH) is an inflammatory protein implicated in pathogenesis of these three infections, thereby making them attractive drug targets.Methods: PAF-AH sequences were retrieved from UniProt and aligned using Clustal Omega. Homologous models of parasitic proteins were built based on crystal structure of human PAF-AH and validated using PROCHECK server. Volumes of substrate-binding channel were calculated using the ProteinsPlus program. High throughput virtual screening using Glide program in Schrodinger was done with ZINC drug library against parasitic PAF-AH enzymes. Complexes with best hits were energy-minimized and subjected to 100 ns molecular dynamic simulation and analyzed.Results: PAF-AH enzyme sequences from protozoa Leishmania donovani, Trypanosoma cruzi, Trypanosoma brucei, and human have a minimum of 34% sequence similarity with each other. Corresponding structures show a globular conformation consisting of twisted β-pleated sheets, flanked by α-helices on either side. Catalytic triad of serine-histidine-aspartate is conserved. Substrate-binding channel residues are conserved to an extent, with a lower channel volume in human as compared to target enzymes. Drug screening resulted in identification of three molecules that had better affinities than the substrate to the target enzymes. These molecules fulfill Lipinski’s rules for drug likeness and also bind with less affinity to the human counterpart, thereby establishing a high selective index.Conclusion: Structures of PAF-AH from protozoan parasites and humans belong to the same family of enzymes and have a similar three-dimensional fold. However, they show subtle variations in residue composition, secondary structure composition, substrate-binding channel volume, and conformational stability. These differences result in certain specific molecules being potent inhibitors of the target enzymes while simultaneously having weaker binding to human homologue.Keywords: platelet activating factor acetyl hydrolase, protozoa, drug target, potent inhibitor, leishmaniasis, Leishmania donovani, Chagas disease, Trypanosoma cruzi, sleeping sickness, Trypanosoma brucei, drug efficacy

Neglected diseases, primarily found in tropical regions of the world, present a significant challenge for impoverished populations. Currently, there are 20 diseases considered neglected, which greatly impact the health of affected populations and result in difficult-to-control social and economic consequences. Unfortunately, for the majority of these diseases, there are few or no drugs available for patient treatment, and the few drugs that do exist often lack adequate safety and efficacy. As a result, there is a pressing need to discover and design new drugs to address these neglected diseases. This requires the identification of different targets and interactions to be studied. In recent years, there has been a growing focus on studying enzyme covalent inhibitors as a potential treatment for neglected diseases. In this review, we will explore examples of how these inhibitors have been used to target Human African Trypanosomiasis, Chagas disease, and Malaria, highlighting some of the most promising results so far. Ultimately, this review aims to inspire medicinal chemists to pursue the development of new drug candidates for these neglected diseases, and to encourage greater investment in research in this area. [ABSTRACT FROM AUTHOR]

Current medication therapy for leishmaniasis and trypanosomiasis remains a major challenge due to its limited efficacy, significant adverse effects, and inaccessibility. Consequently, locating affordable and effective medications is a pressing concern. Because of their easy-to-understand structure and high functionalization potential, chalcones are promising candidates for use as bioactive agents. Thirteen synthetic ligustrazine-containing chalcones were evaluated for their ability to inhibit the growth of leishmaniasis and trypanosomiasis in etiologic agents. The tetramethylpyrazine (TMP) analogue ligustrazine was chosen as the central moiety for the synthesis of these chalcone compounds. The most effective compound (EC50 = 2.59 µM) was the chalcone derivative 2c, which featured a pyrazin-2-yl amino on the ketone ring and a methyl substitution. Multiple actions were observed for certain derivatives, including 1c, 2a–c, 4b, and 5b, against all strains tested. Eflornithine served as a positive control, and three ligustrazine-based chalcone derivatives, including 1c, 2c, and 4b, had a higher relative potency. Compounds 1c and 2c are particularly efficacious; even more potent than the positive control, they are therefore promising candidates for the treatment of trypanosomiasis and leishmaniasis. [ABSTRACT FROM AUTHOR]

This study investigated the antitrypanosomal activity of Argemone mexicana extract and fractions in the animal model of Trypanosoma brucei brucei infection.

Due to the lack of specific vaccines, management of the trypanosomatid-caused neglected tropical diseases (sleeping sickness, Chagas disease and leishmaniasis) relies exclusively on pharmacological treatments. Current drugs against them are scarce, old and exhibit disadvantages, such as adverse effects, parenteral administration, chemical instability and high costs which are often unaffordable for endemic low-income countries. Discoveries of new pharmacological entities for the treatment of these diseases are scarce, since most of the big pharmaceutical companies find this market unattractive. In order to fill the pipeline of compounds and replace existing ones, highly translatable drug screening platforms have been developed in the last two decades. Thousands of molecules have been tested, including nitroheterocyclic compounds, such as benznidazole and nifurtimox, which had already provided potent and effective effects against Chagas disease. More recently, fexinidazole has been added as a new drug against African trypanosomiasis. Despite the success of nitroheterocycles, they had been discarded from drug discovery campaigns due to their mutagenic potential, but now they represent a promising source of inspiration for oral drugs that can replace those currently on the market. The examples provided by the trypanocidal activity of fexinidazole and the promising efficacy of the derivative DNDi-0690 against leishmaniasis seem to open a new window of opportunity for these compounds that were discovered in the 1960s. In this review, we show the current uses of nitroheterocycles and the novel derived molecules that are being synthesized against these neglected diseases. [ABSTRACT FROM AUTHOR]

Trypanosomiasis is a serious disease that affects both humans and animals, causing social and economic losses. Efforts to find new therapeutic approaches are warranted to improve treatment options. Therefore, the purpose of this communication includes the phytochemical screening of a methanolic extract of Garcinia kola nuts and the in vivo evaluation of its biological activity against rats infected with Trypanosoma brucei brucei and treated with 4 different concentrations of the extract (0.01, 0.1, 1, and 10 mg/kg). Treatment with suramin served as a positive control, while the negative control received no drug. Since the general toxicity of the extract could be ruled out, efficacy was evaluated based on physiological changes, such as induction of trypanosome parasitemia, influence on body temperature, and body weight. Survival was assessed during this study. Physical parameters, behavioral characteristics, and various hematological indices were also monitored. Based on the (patho)physiological and behavioral parameters (e.g., no parasitemia, no increase in body temperature, an increase in body weight, no loss of condition, no alopecia, and no gangrene), the efficacy of the extract was evident, which was also confirmed by 100% survival, while in the negative control, all rats died during the observation period. Since overall very similar results were obtained as a result of treatment with the established suramin, the in vivo antitrypanosomal activity of a methanolic extract of G. kola nuts on rats can be demonstrated in this communication. This opens the way, for example, for further development of drug formulations based on this methanolic extract. [ABSTRACT FROM AUTHOR]

Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world’s poorest people: African trypanosomiasis or sleeping sickness, American trypanosomiasis or Chagas disease and different types of leishmaniasis. Different metabolic pathways have been targeted to find antitrypanosomatid drugs, including polyamine metabolism. Since their discovery, the naturally occurring polyamines, putrescine, spermidine and spermine, have been considered important metabolites involved in cell growth. With a complex metabolism involving biosynthesis, catabolism and interconversion, the synthesis of putrescine and spermidine was targeted by thousands of compounds in an effort to produce cell growth blockade in tumor and infectious processes with limited success. However, the discovery of eflornithine (DFMO) as a curative drug against sleeping sickness encouraged researchers to develop new molecules against these diseases. Polyamine synthesis inhibitors have also provided insight into the peculiarities of this pathway between the host and the parasite, and also among different trypanosomatid species, thus allowing the search for new specific chemical entities aimed to treat these diseases and leading to the investigation of target-based scaffolds. The main molecular targets include the enzymes involved in polyamine biosynthesis (ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine synthase), enzymes participating in their uptake from the environment, and the enzymes involved in the redox balance of the parasite. In this review, we summarize the research behind polyamine-based treatments, the current trends, and the main challenges in this field.

Currently, Chagas disease, or human American trypanosomiasis, affects around 900 people in Portugal, mostly Brazilian immigrants, the main foreign population residing in the country. This article presents a historical inquiry on the first receptions of the Brazilian discovery of Chagas disease in Portugal, a country that had scientists interested in the study of tropical diseases, namely sleeping sickness, or African trypanosomiasis, which affected epidemic in the African colonies of Angola and the island of Príncipe. The time frame of this study is limited between 1909, the date of Carlos Chagas' scientific discovery, and 1924, the year in which the already internationally renowed Brazilian physician, then traveling through Europe, was invited by Portuguese colleagues to give a lecture on American trypanosomiasis in Lisbon. In methodological terms, this article was written based on the work of scrutinizing publications in scientific periodicals, inaugural theses defended in medical schools and Portuguese press news.

This study explored a series of resorcinol derivatives originally identified as heat shock protein 90 inhibitors for activity against protozoan parasites. The repurposing of this series revealed that some of these compounds are active against chloroquine-sensitive Plasmodium falciparum (3D7) and Trypanosoma brucei brucei strains with IC50 values below 10 μM without obvious cytotoxic effects against human cervix adenocarcinoma (HeLa) cells at 25 μM. [ABSTRACT FROM AUTHOR]

After 100 years of chemotherapy with impractical and toxic drugs, an oral cure for human African trypanosomiasis (HAT) is available: Fexinidazole. In this case, we review the history of drug discovery for HAT with special emphasis on the discovery, pre-clinical development, and operational challenges of the clinical trials of fexinidazole. The screening of the Drugs for Neglected Diseases initiative (DNDi) HAT-library by the Swiss TPH had singled out fexinidazole, originally developed by Hoechst (now Sanofi), as the most promising of a series of over 800 nitroimidazoles and related molecules. In cell culture, fexinidazole has an IC50 of around 1 µM against Trypanosoma brucei and is more than 100-fold less toxic to mammalian cells. In the mouse model, fexinidazole cures both the first, haemolymphatic, and the second, meningoencephalitic stage of the infection, the latter at 100 mg/kg twice daily for 5 days. In patients, the clinical trials managed by DNDi and supported by Swiss TPH mainly conducted in the Democratic Republic of the Congo demonstrated that oral fexinidazole is safe and effective for use against first- and early second-stage sleeping sickness. Based on the positive opinion issued by the European Medicines Agency in 2018, the WHO has released new interim guidelines for the treatment of HAT including fexinidazole as the new therapy for first-stage and non-severe second-stage sleeping sickness caused by Trypanosoma brucei gambiense (gHAT). This greatly facilitates the diagnosis and treatment algorithm for gHAT, increasing the attainable coverage and paving the way towards the envisaged goal of zero transmission by 2030. [ABSTRACT FROM AUTHOR]

Abstract Objective Currently, the only available staging criterion for T. b. rhodesiense requires a lumber puncture to collect and later examine cerebrospinal fluid (CSF). This study examined the potential of plasma Neuron-Specific Enolase (NSE) in discriminating between early and late-stage patients. Results When median NSE levels were compared between early and late-stage patients, results showed a significant (P 0.9) in NSE levels were observed between early-stage patients (300 ng/mL) and controls (454 ng/mL). We used Receiver Operator Characteristic (ROC) curves to explore the likelihood of using plasma NSE as a potential stage biomarker in discriminating between early and late-stage HAT patients. Our results showed that NSE demonstrated an area under the curve (AUC) of 0.702 (95% CI 0.583–0.830). A high staging accuracy for NSE was obtained by using a cutoff of > 346.5 ng/mL with a sensitivity of 68.6% (95% CI 55–79.7%) and a specificity of 93.3% (95% CI 70.2–99.7%). Although our results demonstrate that plasma NSE is upregulated in T. b. rhodesiense sleeping sickness patients, its value in discriminating between late and early-stage patients is limited. However, future studies could consider improving its specificity by combining it with other identified plasma biomarkers.

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.

Neglected diseases (NDs) are treated with a less varied range of drugs, with high cost and toxicity, which makes the search for therapeutic alternatives important. In this context, plants, such as those from the genus Zanthoxylum, can be promising due to active substances in their composition. This study evaluates the potential of species from this genus to treat NDs. Initially, a protocol was developed to carry out a systematic review approved by Prospero (CRD42020200438). The databases PubMed, BVS, Scopus, Science Direct, and Web of Science were used with the following keywords: “zanthoxylum,” “xanthoxylums,” “fagaras,” “leishmaniasis,” “chagas disease,” “malaria,” and “African trypanosomiasis.” Two independent evaluators analyzed the title and abstract of 166 articles, and 122 were excluded due to duplicity or for not meeting the inclusion criteria. From the 44 selected articles, results of in vitro/in vivo tests were extracted. In vitro studies showed that Z. rhoifolium, through the alkaloid nitidine, was active against Plasmodium (IC50 10 and >30, respectively). For Chagas disease, the promising species (IC50

Nitro-containing compounds are a well-known class of anti-infective agents, especially in the field of anti-parasitic drug discovery. HAT or sleeping sickness is a neglected tropical disease caused by a protozoan parasite, Trypanosoma brucei. Following the approval of fexinidazole as the first oral treatment for both stages of T. b. gambiense HAT, there is an increased interest in developing new nitro-containing compounds against parasitic diseases. In our previous projects, we synthesized several megazole derivatives that presented high activity against Leishmania major promastigotes. Here, we screened and evaluated their trypanocidal activity. Most of the compounds showed submicromolar IC50 against the BSF form of T. b. rhodesiense (STIB 900). To the best of our knowledge, compound 18c is one of the most potent nitro-containing agents reported against HAT in vitro. Compound 18g revealed an acceptable cure rate in the acute mouse model of HAT, accompanied with noteworthy in vitro activity against T. brucei, T. cruzi, and L. donovani. Taken together, these results suggest that these compounds are promising candidates to evaluate their pharmacokinetic and biological profiles in the future. [ABSTRACT FROM AUTHOR]

Human trypanosomiasis affects nearly eight million people worldwide, causing great economic and social impact, mainly in endemic areas. T. cruzi and T. brucei are protozoan parasites that present efficient mechanisms of immune system evasion, leading to disease chronification. Currently, there is no vaccine, and chemotherapy is effective only in the absence of severe clinical manifestations. Nevertheless, resistant phenotypes to chemotherapy have been described in protozoan parasites, associated with cross-resistance to other chemically unrelated drugs. Multidrug resistance is multifactorial, involving: (i) drug entry, (ii) activation, (iii) metabolism and (iv) efflux pathways. In this context, ABC transporters, initially discovered in resistant tumor cells, have drawn attention in protozoan parasites, owing to their ability to decrease drug accumulation, thus mitigating their toxic effects. The discovery of these transporters in the Trypanosomatidae family started in the 1990s; however, few members were described and functionally characterized. This review contains a brief history of the main ABC transporters involved in resistance that propelled their investigation in Trypanosoma species, the main efflux modulators, as well as ABC genes described in T. cruzi and T. brucei according to the nomenclature HUGO. We hope to convey the importance that ABC transporters play in parasite physiology and chemotherapy resistance. [ABSTRACT FROM AUTHOR]

Apolipoprotein-L1 (APOL1) is a membrane-interacting protein induced by inflammation, which confers human resistance to infection by African trypanosomes. APOL1 kills Trypanosoma brucei through induction of apoptotic-like parasite death, but two T. brucei clones acquired resistance to APOL1, allowing them to cause sleeping sickness. An APOL1 C-terminal sequence alteration, such as occurs in natural West African variants G1 and G2, restored human resistance to these clones. However, APOL1 unfolding induced by G1 or G2 mutations enhances protein hydrophobicity, resulting in kidney podocyte dysfunctions affecting renal filtration. The mechanism involved in these dysfunctions is debated. The ability of APOL1 to generate ion pores in trypanosome intracellular membranes or in synthetic membranes was provided as an explanation. However, transmembrane insertion of APOL1 strictly depends on acidic conditions, and podocyte cytopathology mainly results from secreted APOL1 activity on the plasma membrane, which occurs under non-acidic conditions. In this review, I argue that besides inactivation of APOL3 functions in membrane dynamics (fission and fusion), APOL1 variants induce inflammation-linked podocyte toxicity not through pore formation, but through plasma membrane disturbance resulting from increased interaction with cholesterol, which enhances cation channels activity. A natural mutation in the membrane-interacting domain (N264K) abrogates variant APOL1 toxicity at the expense of slightly increased sensitivity to trypanosomes, further illustrating the continuous mutual adaptation between host and parasite.

We integrated sleeping sickness case detection into the primary healthcare system in 2 health districts in the Democratic Republic of the Congo. We replaced a less field-friendly serologic test with a rapid diagnostic test, which was followed up by human African trypanosomiasis microscopic testing, and used a mixed costing methodology to estimate costs from a healthcare provider perspective. We screened a total of 18,225 persons and identified 27 new cases. Average financial cost (i.e., actual expenditures) was US $6.70/person screened and $4,464/case diagnosed and treated. Average economic cost (i.e., value of resources foregone that could have been used for other purposes) was $9.40/person screened and $6,138/case diagnosed and treated. Our study shows that integrating sleeping sickness surveillance into the primary healthcare system is feasible and highlights challenges in completing the diagnostic referral process and developing a context-adapted diagnostic algorithm for the large-scale implementation of this strategy in a sustainable and low-cost manner.

Neglected diseases, primarily found in tropical regions of the world, present a significant challenge for impoverished populations. Currently, there are 20 diseases considered neglected, which greatly impact the health of affected populations and result in difficult-to-control social and economic consequences. Unfortunately, for the majority of these diseases, there are few or no drugs available for patient treatment, and the few drugs that do exist often lack adequate safety and efficacy. As a result, there is a pressing need to discover and design new drugs to address these neglected diseases. This requires the identification of different targets and interactions to be studied. In recent years, there has been a growing focus on studying enzyme covalent inhibitors as a potential treatment for neglected diseases. In this review, we will explore examples of how these inhibitors have been used to target Human African Trypanosomiasis, Chagas disease, and Malaria, highlighting some of the most promising results so far. Ultimately, this review aims to inspire medicinal chemists to pursue the development of new drug candidates for these neglected diseases, and to encourage greater investment in research in this area.

Current medication therapy for leishmaniasis and trypanosomiasis remains a major challenge due to its limited efficacy, significant adverse effects, and inaccessibility. Consequently, locating affordable and effective medications is a pressing concern. Because of their easy-to-understand structure and high functionalization potential, chalcones are promising candidates for use as bioactive agents. Thirteen synthetic ligustrazine-containing chalcones were evaluated for their ability to inhibit the growth of leishmaniasis and trypanosomiasis in etiologic agents. The tetramethylpyrazine (TMP) analogue ligustrazine was chosen as the central moiety for the synthesis of these chalcone compounds. The most effective compound (EC50 = 2.59 µM) was the chalcone derivative 2c, which featured a pyrazin-2-yl amino on the ketone ring and a methyl substitution. Multiple actions were observed for certain derivatives, including 1c, 2a–c, 4b, and 5b, against all strains tested. Eflornithine served as a positive control, and three ligustrazine-based chalcone derivatives, including 1c, 2c, and 4b, had a higher relative potency. Compounds 1c and 2c are particularly efficacious; even more potent than the positive control, they are therefore promising candidates for the treatment of trypanosomiasis and leishmaniasis.

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 [ABSTRACT FROM AUTHOR]

As a contribution to the existing literature on deliberate or unintended neglect, concealment and ignorance regarding significant and enduring public health problems—produced by economic marginality, lack of political power and institutional failures affecting specific places and groups—this article discusses the history of epidemic sleeping sickness and endemic onchocerciasis in colonial northern Ghana from 1909 to 1957. Despite accumulating evidence of their serious impacts on the health of northern communities, and calls to action on the part of some health officials, both diseases were only officially recognised as significant risks when it was no longer politically possible to deny them. The particular histories of each disease, in the same region over the same decades, reveal two comparable and interrelated trajectories of neglect. [ABSTRACT FROM AUTHOR]

Eflornithine is a recommended treatment against late-stage gambiense human African trypanosomiasis, a neglected tropical disease. Standard dosing of eflornithine consists of repeated intravenous infusions of a racemic mixture of L- and D-eflornithine. Data from three clinical studies, (i) eflornithine intravenous monotherapy, (ii) nifurtimox-eflornithine combination therapy, and (iii) eflornithine oral monotherapy, were pooled and analyzed using a time-to-event pharmacodynamic modeling approach, supported by in vitro activity data of the individual enantiomers. Our aim was to assess (i) the efficacy of the eflornithine regimens in a time-to-event analysis and (ii) the feasibility of an L-eflornithine-based therapy integrating clinical and preclinical data. A pharmacodynamic time-to-event model was used to estimate the total dose of eflornithine, associated with 50% reduction in baseline hazard, when administered as monotherapy or in the nifurtimox-eflornithine combination therapy. The estimated total doses were 159, 60 and 291 g for intravenous eflornithine monotherapy, nifurtimox-eflornithine combination therapy and oral eflornithine monotherapy, respectively. Simulations suggested that L-eflornithine achieves a higher predicted median survival, compared to when racemate is administered, as treatment against late-stage gambiense human African trypanosomiasis. Our findings showed that oral L-eflornithine-based monotherapy would not result in adequate efficacy, even at high dose, and warrants further investigations to assess the potential of oral L-eflornithine-based treatment in combination with other treatments such as nifurtimox. An all-oral eflornithine-based regimen would provide easier access to treatment and reduce burden on patients and healthcare systems in gambiense human African trypanosomiasis endemic areas. [ABSTRACT FROM AUTHOR]