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Molecules (Basel, Switzerland) May 2024Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected... (Review)
Review
Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected Tropical Diseases affecting millions of people worldwide, mainly in vulnerable territories of tropical and subtropical areas. In general, current treatments against these diseases are old-fashioned, showing adverse effects and loss of efficacy due to misuse or overuse, thus leading to the emergence of resistance. For these reasons, searching for new antitrypanosomatid drugs has become an urgent necessity, and different metabolic pathways have been studied as potential drug targets against these parasites. Considering that trypanosomatids possess a unique redox pathway based on the trypanothione molecule absent in the mammalian host, the key enzymes involved in trypanothione metabolism, trypanothione reductase and trypanothione synthetase, have been studied in detail as druggable targets. In this review, we summarize some of the recent findings on the molecules inhibiting these two essential enzymes for and viability.
Topics: NADH, NADPH Oxidoreductases; Humans; Amide Synthases; Trypanosoma; Glutathione; Animals; Spermidine; Leishmania; Trypanocidal Agents; Leishmaniasis; Trypanosomatina; Protozoan Proteins; Chagas Disease
PubMed: 38792079
DOI: 10.3390/molecules29102214 -
Bioorganic & Medicinal Chemistry May 2024In previous studies, we developed anti-trypanosome tubulin inhibitors with promising in vitro selectivity and activity against Human African Trypanosomiasis (HAT)....
In previous studies, we developed anti-trypanosome tubulin inhibitors with promising in vitro selectivity and activity against Human African Trypanosomiasis (HAT). However, for such agents, oral activity is crucial. This study focused on further optimizing these compounds to enhance their ligand efficiency, aiming to reduce bulkiness and hydrophobicity, which should improve solubility and, consequently, oral bioavailability. Using Trypanosoma brucei brucei cells as the parasite model and human normal kidney cells and mouse macrophage cells as the host model, we evaluated 30 new analogs synthesized through combinatorial chemistry. These analogs have fewer aromatic moieties and lower molecular weights than their predecessors. Several new analogs demonstrated ICs in the low micromolar range, effectively inhibiting trypanosome cell growth without harming mammalian cells at the same concentration. We conducted a detailed structure-activity relationship (SAR) analysis and a docking study to assess the compounds' binding affinity to trypanosome tubulin homolog. The results revealed a correlation between binding energy and anti-Trypanosoma activity. Importantly, compound 7 displayed significant oral activity, effectively inhibiting trypanosome cell proliferation in mice.
PubMed: 38762979
DOI: 10.1016/j.bmc.2024.117751 -
Sleep Advances : a Journal of the Sleep... 2024In November 1965, Michel Jouvet accepted me into his laboratory in Lyon as a medical student at a time when sleep research was an adventure. After 4 years of...
In November 1965, Michel Jouvet accepted me into his laboratory in Lyon as a medical student at a time when sleep research was an adventure. After 4 years of investigations in cats, I obtained my medical doctorate. Being a military physician, I was posted to Antarctica for wintering over and was initiated by Jean Rivolier into the psychology of small isolated human groups. I recorded 180 polysomnographic (PSG) nights in eight of my companions. This was my first contribution to research on human sleep under extreme environments and conditions. I then entered René Hénane's military thermophysiology laboratory, where I analyzed thermal exchanges during human sleep in the heat. Back to the cold, I spent 2 years in Canada and analyzed sleep during the Arctic winter under the direction of Manny W. Radomski, who headed the Defense and Civil Institute of Environmental Medicine and judged my PhD dissertation along with my first two mentors. Throughout my career, I worked in collaboration with Manny Radomski under the auspices of the Franco-Canadian Accord for Defence Research. We studied sleep and exercise, sleep deprivation, and recovery with and without chemical help. He also gave me support during several investigations in Africa. There, I studied normal sleep under various tropical climates (warm and dry in Niger, warm and humid in Côte d'Ivoire and Congo, temperate mid-mountain in Angola). I determined that human African trypanosomiasis, the ravaging sleeping sickness or tsetse disease, is not a hypersomnia, but a disorder of circadian rhythms, notably in the sleep-wake cycle.
PubMed: 38737795
DOI: 10.1093/sleepadvances/zpae025 -
Parasites & Vectors May 2024Animal African trypanosomiasis, which is caused by different species of African trypanosomes, is a deadly disease in livestock. Although African trypanosomes are often...
BACKGROUND
Animal African trypanosomiasis, which is caused by different species of African trypanosomes, is a deadly disease in livestock. Although African trypanosomes are often described as blood-borne parasites, there have been recent reappraisals of the ability of these parasites to reside in a wide range of tissues. However, the majority of those studies were conducted on non-natural hosts infected with only one species of trypanosome, and it is unclear whether a similar phenomenon occurs during natural animal infections, where multiple species of these parasites may be present.
METHODS
The infective trypanosome species in the blood and other tissues (adipose and skin) of a natural host (cows, goats and sheep) were determined using a polymerase chain reaction-based diagnostic.
RESULTS
The animals were found to harbour multiple species of trypanosomes. Different patterns of distribution were observed within the host tissues; for instance, in some animals, the blood was positive for the DNA of one species of trypanosome and the skin and adipose were positive for the DNA of another species. Moreover, the rate of detection of trypanosome DNA was highest for skin adipose and lowest for the blood.
CONCLUSIONS
The findings reported here emphasise the complexity of trypanosome infections in a natural setting, and may indicate different tissue tropisms between the different parasite species. The results also highlight the need to include adipose and skin tissues in future diagnostic and treatment strategies.
Topics: Animals; Goats; Trypanosomiasis, African; Adipose Tissue; Trypanosoma; Skin; Sheep; Goat Diseases; Cattle; Polymerase Chain Reaction; Sheep Diseases; DNA, Protozoan; Cattle Diseases
PubMed: 38734633
DOI: 10.1186/s13071-024-06277-7 -
Molecules (Basel, Switzerland) Apr 2024Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current...
Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current antiprotozoal treatments and the lack of approved vaccines. Considering the demand for novel therapeutic drugs, a series of BODIPY derivatives with several functionalizations at the , 2 and/or 6 positions of the core were synthesized and characterized. The in vitro activity against and parasites was carried out alongside a human healthy cell line (MRC-5) to establish selectivity indices (SIs). Notably, the -substituted BODIPY, with 1-dimethylaminonaphthalene () and anthracene moiety (), were the most active against , displaying IC = 4.84 and 5.41 μM, with a 16 and 18-fold selectivity over MRC-5 cells, respectively. In contrast, the mono-formylated analogues and exhibited the highest toxicity (IC = 2.84 and 6.17 μM, respectively) and selectivity (SI = 24 and 11, respectively) against . Further insights on the activity of these compounds were gathered from molecular docking studies. The results suggest that these BODIPYs act as competitive inhibitors targeting the NADPH/NADP linkage site of the pteridine reductase (PR) enzyme. Additionally, these findings unveil a range of quasi-degenerate binding complexes formed between the PRs and the investigated BODIPY derivatives. These results suggest a potential correlation between the anti-parasitic activity and the presence of multiple configurations that block the same site of the enzyme.
Topics: Boron Compounds; Trypanosoma brucei brucei; Humans; Molecular Docking Simulation; Antiprotozoal Agents; Leishmania major; Drug Design; Structure-Activity Relationship; Cell Line; Molecular Structure; Trypanocidal Agents; Oxidoreductases
PubMed: 38731562
DOI: 10.3390/molecules29092072 -
PLoS Neglected Tropical Diseases May 2024Sleeping sickness caused by Trypanosoma brucei rhodesiense is a fatal disease and endemic in Southern and Eastern Africa. There is an urgent need to develop novel...
BACKGROUND
Sleeping sickness caused by Trypanosoma brucei rhodesiense is a fatal disease and endemic in Southern and Eastern Africa. There is an urgent need to develop novel diagnostic and control tools to achieve elimination of rhodesiense sleeping sickness which might be achieved through a better understanding of trypanosome gene expression and genetics using endemic isolates. Here, we describe transcriptome profiles and population structure of endemic T. b. rhodesiense isolates in human blood in Malawi.
METHODOLOGY
Blood samples of r-HAT cases from Nkhotakota and Rumphi foci were collected in PaxGene tubes for RNA extraction before initiation of r-HAT treatment. 100 million reads were obtained per sample, reads were initially mapped to the human genome reference GRCh38 using HiSat2 and then the unmapped reads were mapped against Trypanosoma brucei reference transcriptome (TriTrypDB54_TbruceiTREU927) using HiSat2. Differential gene expression analysis was done using the DeSeq2 package in R. SNP calling from reads that were mapped to the T. brucei genome was done using GATK in order to identify T.b. rhodesiense population structure.
RESULTS
24 samples were collected from r-HAT cases of which 8 were from Rumphi and 16 from Nkhotakota foci. The isolates from Nkhotakota were enriched with transcripts for cell cycle arrest and stumpy form markers, whereas isolates in Rumphi focus were enriched with transcripts for folate biosynthesis and antigenic variation pathways. These parasite focus-specific transcriptome profiles are consistent with the more virulent disease observed in Rumphi and a less symptomatic disease in Nkhotakota associated with the non-dividing stumpy form. Interestingly, the Malawi T.b. rhodesiense isolates expressed genes enriched for reduced cell proliferation compared to the Uganda T.b. rhodesiense isolates. PCA analysis using SNPs called from the RNAseq data showed that T. b. rhodesiense parasites from Nkhotakota are genetically distinct from those collected in Rumphi.
CONCLUSION
Our results suggest that the differences in disease presentation in the two foci is mainly driven by genetic differences in the parasites in the two major endemic foci of Rumphi and Nkhotakota rather than differences in the environment or host response.
Topics: Malawi; Humans; Trypanosoma brucei rhodesiense; Transcriptome; Trypanosomiasis, African; Gene Expression Profiling; Polymorphism, Single Nucleotide; Male
PubMed: 38701067
DOI: 10.1371/journal.pntd.0011516 -
Fitoterapia Apr 2024Anogeissus leiocarpus (DC.) Guill. & Perr. belongs to the family Combretaceae and is used both by African traditional medical practitioners and livestock rearers to... (Review)
Review
Anogeissus leiocarpus (DC.) Guill. & Perr. belongs to the family Combretaceae and is used both by African traditional medical practitioners and livestock rearers to treat diseases such as African trypanosomiasis, animal diarrhoea, asthma, cancer, cough, diabetes, dysentery, erectile dysfunction, fever, giardiasis, helminthiases, meningitis, menstrual disorders, monkeypox, oral infections, poliomyelitis, sickle cell anaemia, snake bites, toothache, urinary schistosomiasis, and yellow fever. Some of these activities have been associated with the presence of polyphenols in the plant which include ellagic acid derivatives, flavonoids, stilbenes, tannins, and triterpenes. Several bioactive molecules have been identified from A. leiocarpus. These include the main active constituents, ellagitannins, ellagic acid derivates, flavonoids and triterpenes. Pharmacological studies have confirmed its antibacterial, antifungal, antihyperglycemic, antihypertensive, antimalarial, antioxidative, antiparasitic, antitumour and anti-ulcer effects. The stem bark has been investigated mainly for biological activities and phytochemistry, and it is the most mentioned plant part highlighted by the traditional users in ethnomedicinal surveys. In vitro and in vivo models, which revealed a wide range of pharmacological actions against parasites causing helminthiasis, leishmaniasis, malaria and trypanosomiasis, have been used to study compounds from A. leiocarpus. Because of its uses in African traditional medicine and veterinary practices, A. leiocarpus has received considerable attention from researchers. The current review provides a comprehensive overview and critical appraisal of scientific reports on A. leiocarpus, covering its traditional uses, pharmacological activities and phytochemistry.
PubMed: 38692415
DOI: 10.1016/j.fitote.2024.105979 -
PLoS Neglected Tropical Diseases May 2024
Topics: Humans; Trypanosomiasis, African; Disease Eradication; Animals; Africa; Neglected Diseases
PubMed: 38691551
DOI: 10.1371/journal.pntd.0012091 -
International Journal of Molecular... Apr 2024In recent decades, neglected tropical diseases and poverty-related diseases have become a serious health problem worldwide. Among these pathologies, human African...
In recent decades, neglected tropical diseases and poverty-related diseases have become a serious health problem worldwide. Among these pathologies, human African trypanosomiasis, and malaria present therapeutic problems due to the onset of resistance, toxicity problems and the limited spectrum of action. In this drug discovery process, rhodesain and falcipain-2, of and , are currently considered the most promising targets for the development of novel antitrypanosomal and antiplasmodial agents, respectively. Therefore, in our study we identified a novel lead-like compound, i.e., inhibitor , which we proved to be active against both targets, with a = 5.06 µM towards rhodesain and an IC = 40.43 µM against falcipain-2.
Topics: Humans; Antimalarials; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Malaria; Nitriles; Plasmodium falciparum; Protozoan Proteins; Trypanocidal Agents; Trypanosoma brucei rhodesiense; Trypanosomiasis, African
PubMed: 38673995
DOI: 10.3390/ijms25084410 -
International Journal of Molecular... Apr 2024Chagas disease is one of the world's neglected tropical diseases, caused by the human pathogenic protozoan parasite . There is currently a lack of effective and...
Chagas disease is one of the world's neglected tropical diseases, caused by the human pathogenic protozoan parasite . There is currently a lack of effective and tolerable clinically available therapeutics to treat this life-threatening illness and the discovery of modern alternative options is an urgent matter. glucokinase (GlcK) is a potential drug target because its product, d-glucose-6-phosphate, serves as a key metabolite in the pentose phosphate pathway, glycolysis, and gluconeogenesis. In 2019, we identified a novel cluster of GlcK inhibitors that also exhibited anti- efficacy called the 3-nitro-2-phenyl-2-chromene analogues. This was achieved by performing a target-based high-throughput screening (HTS) campaign of 13,040 compounds. The selection criteria were based on first determining which compounds strongly inhibited GlcK in a primary screen, followed by establishing on-target confirmed hits from a confirmatory assay. Compounds that exhibited notable in vitro trypanocidal activity over the infective form (trypomastigotes and intracellular amastigotes) co-cultured in NIH-3T3 mammalian host cells, as well as having revealed low NIH-3T3 cytotoxicity, were further considered. Compounds and were determined to inhibit GlcK quite well with IC values of 6.1 µM and 4.8 µM, respectively. Illuminated by these findings, we herein screened a small compound library consisting of thirteen commercially available 3-nitro-2-phenyl-2-chromene analogues, two of which were and (compounds and , respectively). Twelve of these compounds had a one-point change from the chemical structure of . The analogues were run through a similar primary screening and confirmatory assay protocol to our previous HTS campaign. Subsequently, three in vitro biological assays were performed where compounds were screened against (a) (Tulahuen strain) infective form co-cultured within NIH-3T3 cells, (b) (427 strain) bloodstream form, and (c) NIH-3T3 host cells alone. We report on the GlcK inhibitor constant determinations, mode of enzyme inhibition, in vitro antitrypanosomal IC determinations, and an assessment of structure-activity relationships. Our results reveal that the 3-nitro-2-phenyl--chromene scaffold holds promise and can be further optimized for both Chagas disease and human African trypanosomiasis early-stage drug discovery research.
Topics: Animals; Humans; Mice; Benzopyrans; Chagas Disease; Drug Discovery; Enzyme Inhibitors; Glucokinase; High-Throughput Screening Assays; Molecular Docking Simulation; NIH 3T3 Cells; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi; Protein Kinase Inhibitors
PubMed: 38673904
DOI: 10.3390/ijms25084319