Discovery and Development of an Advanced Lead for the Treatment of African Trypanosomiasis.

African trypanosomiasis is a widespread disease of human and veterinary importance caused by various with a globally devastating impact and a need for novel treatment options. We here provide a comprehensive preclinical evaluation of nucleoside analogues, 6-thioether-modified tubercidins, with curative activity against African trypanosomiasis. Promising hits were identified following screening against the most relevant trypanosome species.

Environmental impacts of drugs against parasitic vector-borne diseases and the need to integrate sustainability into their development and use.

Background: The current scientific discourse on environmental impacts of veterinary medicines mostly focuses on ectoparasiticides. Meanwhile, the environmental impacts of widely prescribed drugs for the treatment of human and animal parasitic vector-borne diseases (PVBD) remain largely unexplored. There is thus a need for evidence-based information to support guidelines and protocols for sustainable One Health PVBD drug development and use, while promoting greener research practices.

Antitrypanosomal and antileishmanial activity of compounds from some Nigerian plants.

Ten compounds, six extracts and five fractions obtained from three Nigerian plants were assayed for their in vitro antitrypanosomal and antileishmanial activities. Each plant was extacted with hexane, ethyl acetate, and methanol. Isolated compounds were characterized and identified based on their NMR chemical shifts and comparison to literature reports.

The activities of suaveolol and other compounds from Hyptis suaveolens and Momordica charantia against the aetiological agents of African trypanosomiasis, leishmaniasis and malaria.

African trypanosomiasis and malaria are among the most severe health challenges to humans and livestock in Africa and new drugs are needed. Leaves of Hyptis suaveolens Kuntze (Lamiaceae) and Momordica charantia L. (Cucurbitaceae) were extracted with hexane, ethyl acetate, and then methanol, and subjected to silica gel column chromatography.

Drug resistance in animal trypanosomiases: Epidemiology, mechanisms and control strategies.

Animal trypanosomiasis (AT) is a complex of veterinary diseases known under various names such as nagana, surra, dourine and mal de caderas, depending on the country, the infecting trypanosome species and the host. AT is caused by parasites of the genus Trypanosoma, and the main species infecting domesticated animals are T. brucei brucei, T.

Mapping the transporter-substrate interactions of the Trypanosoma cruzi NB1 nucleobase transporter reveals the basis for its high affinity and selectivity for hypoxanthine and guanine and lack of nucleoside uptake.

Trypanosoma cruzi is a protozoan parasite and the etiological agent of Chagas disease, a debilitating and sometimes fatal disease that continues to spread to new areas. Yet, Chagas disease is still only treated with two related nitro compounds that are insufficiently effective and cause severe side effects. Nucleotide metabolism is one of the known vulnerabilities of T.

Pyrimidine salvage in as a target for new treatment.

Toxoplasmosis is a common protozoan infection that can have severe outcomes in the immunocompromised and during pregnancy, but treatment options are limited. Recently, nucleotide metabolism has received much attention as a target for new antiprotozoal agents and here we focus on pyrimidine salvage by as a drug target. Whereas uptake of [H]-cytidine and particularly [H]-thymidine was at most marginal, [H]-uracil and [H]-uridine were readily taken up.

Human schistosomiasis in Nigeria: present status, diagnosis, chemotherapy, and herbal medicines.

Schistosomiasis is a neglected tropical disease caused by a parasitic, trematode blood fluke of the genus Schistosoma. With 20 million people infected, mostly due to Schistosoma haematobium, Nigeria has the highest burden of schistosomiasis in the world. We review the status of human schistosomiasis in Nigeria regarding its distribution, prevalence, diagnosis, prevention, orthodox and traditional treatments, as well as snail control strategies.

Synthesis and Biophysical and Biological Studies of -Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites.

The AT-rich mitochondrial DNA (kDNA) of trypanosomatid parasites is a target of DNA minor groove binders. We report the synthesis, antiprotozoal screening, and SAR studies of three series of analogues of the known antiprotozoal kDNA binder 2-((4-(4-((4,5-dihydro-1-imidazol-3-ium-2-yl)amino)benzamido)phenyl)amino)-4,5-dihydro-1-imidazol-3-ium (). Bis(2-aminoimidazolines) (1) and bis(2-aminobenzimidazoles) (2) showed micromolar range activity against whereas bisarylimidamides (3) were submicromolar inhibitors of , and .

Novel kinetoplastid-specific cAMP binding proteins identified by RNAi screening for cAMP resistance in .

Cyclic AMP signalling in trypanosomes differs from most eukaryotes due to absence of known cAMP effectors and cAMP independence of PKA. We have previously identified four genes from a genome-wide RNAi screen for resistance to the cAMP phosphodiesterase (PDE) inhibitor NPD-001. The genes were named cAMP Response Protein (CARP) 1 through 4.

Arylimidamides Have Potential for Chemoprophylaxis against Blood-Transmitted Chagas Disease.

Chagas disease (CD) affects over 6 million people worldwide and can be transmitted iatrogenically. Crystal violet (CV) was previously used for pathogen reduction but has harmful side-effects. In the present study, three arylimidamides (AIAs) and CV were used to sterilize mice blood samples experimentally contaminated with bloodstream trypomastigotes (BT) of , at non hemolytic doses.

The Activity of Red Nigerian Propolis and Some of Its Components against and .

Propolis is a resin that is gathered by bees from exudates produced by various plants. Its exact chemical composition depends on the plants available near the hive. Bees use propolis to coat the surfaces of the hive, where it acts as an anti-infective.

Phenotypic Evaluation of Nucleoside Analogues against Infection: In Vitro and In Vivo Approaches.

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is a serious public health problem. Current treatment is restricted to two drugs, benznidazole and nifurtimox, displaying serious efficacy and safety drawbacks.

The TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2'-Deoxyuridine and Tubercidin Analogues.

Among the scarce validated drug targets against Chagas disease (CD), caused by , the parasite's nucleoside salvage system has recently attracted considerable attention. Although the trypanocidal activity of tubercidin (7-deazapurine) has long been known, the identification of a class of 7-substituted tubercidin analogs with potent in vitro and in vivo activity and much-enhanced selectivity has made nucleoside analogs among the most promising lead compounds against CD. Here, we investigate the recently identified TcrNT2 nucleoside transporter and its potential role in antimetabolite chemotherapy.

Increasing Collaborative Discussion in Case-Based Learning Improves Student Engagement and Knowledge Acquisition.

Background: In the transition from academic to clinical learning, the development of clinical reasoning skills and teamwork is essential, but not easily achieved by didactic teaching only. Case-based learning (CBL) was designed to stimulate discussions of genuine clinical cases and diagnoses but in our initial format (CBL'10) remained predominantly tutor-driven rather than student-directed. However, interactive teaching methods stimulate deep learning and consolidate taught material, and we therefore introduced a more collaborative CBL (cCBL), featuring a structured format with discussions in small breakout groups.

Nucleoside Transport and Nucleobase Uptake Null Mutants in for the Routine Expression and Characterization of Purine and Pyrimidine Transporters.

The study of transporters is highly challenging, as they cannot be isolated or studied in suspension, requiring a cellular or vesicular system, and, when mediated by more than one carrier, difficult to interpret. Nucleoside analogues are important drug candidates, and all protozoan pathogens express multiple equilibrative nucleoside transporter (ENT) genes. We have therefore developed a system for the routine expression of nucleoside transporters, using CRISPR/cas9 to delete both copies of all three nucleoside transporters from (ΔNT1.

Nucleoside analogues for the treatment of animal trypanosomiasis.

Animal trypanosomiasis (AT) is a parasitic disease with high socio-economic impact. Given the limited therapeutic options and problems of toxicity and drug resistance, this study assessed redirecting our previously identified antitrypanosomal nucleosides for the treatment of AT. Promising hits were identified with excellent in vitro activity across all important animal trypanosome species.

Differences in Transporters Rather than Drug Targets Are the Principal Determinants of the Different Innate Sensitivities of and Subgenus Trypanosomes to Diamidines and Melaminophenyl Arsenicals.

The animal trypanosomiases are infections in a wide range of (domesticated) animals with any species of African trypanosome, such as , , , and . Symptoms differ between host and infective species and stage of infection and are treated with a small set of decades-old trypanocides. A complication is that not all trypanosome species are equally sensitive to all drugs and the reasons are at best partially understood.

The Antiprotozoal Activity of Papua New Guinea Propolis and Its Triterpenes.

Profiling a propolis sample from Papua New Guinea (PNG) using high-resolution mass spectrometry indicated that it contained several triterpenoids. Further fractionation by column chromatography and medium-pressure liquid chromatography (MPLC) followed by nuclear magnetic resonance spectroscopy (NMR) identified 12 triterpenoids. Five of these were obtained pure and the others as mixtures of two or three compounds.

Imidazoline- and Benzamidine-Based Trypanosome Alternative Oxidase Inhibitors: Synthesis and Structure-Activity Relationship Studies.

The trypanosome alternative oxidase (TAO), a mitochondrial enzyme involved in the respiration of the bloodstream form trypomastigotes of , is a validated drug target against African trypanosomes. Earlier series of TAO inhibitors having a 2,4-dihydroxy-6-methylbenzoic acid scaffold ("head") and a triphenylphosphonium or quinolin-1-ium cation as a mitochondrion-targeting group ("tail") were shown to be nanomolar inhibitors in enzymatic and cellular assays. We investigated here the effect of different mitochondrion-targeting cations and other scaffold modifications on the in vitro activity of this class of inhibitors.

A Oxopurine Transporter Binds Nucleobases and Nucleosides Using Different Binding Modes.

is unable to synthesize purines de novo, instead salvages them from its environment, inside the host cell, for which they need high affinity carriers. Here, we report the expression of a Equilibrative Nucleoside Transporter, Tg244440, in a strain from which nucleobase transporters have been deleted. Tg244440 transported hypoxanthine and guanine with similar affinity ( ~1 µM), while inosine and guanosine displayed values of 4.