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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 -
Research in Veterinary Science Jul 2024This study reports assessment of the sensitivity of diagnostic techniques to detect T. vivax in experimentally infected cattle. Additionally, it describes T. vivax...
Trypanosoma vivax in and outside cattle blood: Parasitological, molecular, and serological detection, reservoir tissues, histopathological lesions, and vertical transmission evaluation.
This study reports assessment of the sensitivity of diagnostic techniques to detect T. vivax in experimentally infected cattle. Additionally, it describes T. vivax extravascular parasitism during the acute and chronic phases of trypanosomosis and congenital transmission. The T. vivax diagnosis was compared using blood samples collected from the jugular, coccygeal and ear tip veins. For this study, 13 males and two females were infected with ≈ 1 × 10 viable T. vivax trypomastigotes (D0). One animal was kept as a negative control during the entire study. The 13 infected males were euthanized between 14 and 749 days post-infection (DPI). After confirming the cyclicity of both females (9 months of age), they were naturally mated with a bull. One female was euthanized at 840 DPI, and the other at 924 DPI. The two calves, one from each female, were euthanized at six months of age (924 DPI), and the negative control at 924 DPI. During this period, T. vivax in blood was assessed using direct methods (Woo test, cPCR, microscopic examination of fresh wet blood films and parasite quantification - Brener method), and serological methods (IFAT, ELISA, and IA). Tissue samples were collected from the liver, spleen, brain, cerebellum, heart, testicles, epididymis, kidneys, eyeballs, pre-scapular lymph nodes, ear tips, mammary glands, uterus, and ovaries. The protozoan DNA was examined using LAMP. There was no difference in the detection of T. vivax using the Woo test and Brener method among the jugular, coccygeal, and ear tip veins. The sensitivity of the detection methods varied depending on the disease phase. Direct methods (Woo test, Brener method, and cPCR) demonstrated higher sensitivity during the acute phase, while serological methods (IFAT, ELISA, and IA) were more sensitive during the chronic phase. Anti-T. vivax antibodies were detected up to 924 DPI. Tissue evaluation using LAMP demonstrated the presence of T. vivax DNA and associated histopathological changes up to 840 or 924 DPI. Only in mammary glands and ovaries was no DNA detected. The most frequently observed histopathological alteration was lymphohistioplasmocytic inflammatory infiltrate. No transplacental transmission of T. vivax was observed.
Topics: Animals; Cattle; Trypanosoma vivax; Female; Male; Cattle Diseases; Infectious Disease Transmission, Vertical; Trypanosomiasis, African
PubMed: 38776695
DOI: 10.1016/j.rvsc.2024.105290 -
Bioorganic & Medicinal Chemistry Jun 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.
Topics: Animals; Trypanosoma brucei brucei; Trypanocidal Agents; Structure-Activity Relationship; Mice; Humans; Administration, Oral; Cell Proliferation; Molecular Structure; Molecular Docking Simulation; Tubulin; Parasitic Sensitivity Tests; Dose-Response Relationship, Drug; Tubulin Modulators; Trypanosomiasis, African
PubMed: 38762979
DOI: 10.1016/j.bmc.2024.117751 -
Trends in Pharmacological Sciences Jun 2024
Topics: Neuroblastoma; Humans; Eflornithine; Antineoplastic Agents
PubMed: 38749882
DOI: 10.1016/j.tips.2024.04.005 -
International Immunopharmacology Jun 2024Trypanosoma brucei, a causative agent of human and animal trypanosomiasis, regularly switches its major surface antigen to avoid elimination by the immune system....
Trypanosoma brucei, a causative agent of human and animal trypanosomiasis, regularly switches its major surface antigen to avoid elimination by the immune system. Toll-like receptor 9 (TLR9) is a key modulator for resistance to host-infective trypanosomes; however, the underlying molecular mechanism remains indistinct. Thus, we first approached the issue using Tlr9-mutant mice that render them non-responsive to TLR9 agonists. After infection, T cells in the spleens of Tlr9-mutant mice were analyzed by flow cytometry and a reduction in CD8, CD4 T, and NKT cells was observed in Tlr9-mutant mice compared to WT mice. We further found that the responses of inflammatory cytokines in the sera were reduced in Tlr9-mutant mice after T. brucei infection. The underlying molecular mechanism was that T. b. brucei DNA activated TLR9, which consequently upregulated the expression of p38 and ERK/MAPK, resulting in host resistance to trypanosome infection. In conclusion, these findings provide novel insights into the TLR9-mediated host responses to trypanosome infection.
Topics: Toll-Like Receptor 9; Animals; Trypanosoma brucei brucei; Signal Transduction; Trypanosomiasis, African; Mice; Cytokines; Mice, Knockout; Mice, Inbred C57BL; Humans
PubMed: 38749335
DOI: 10.1016/j.intimp.2024.112250 -
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 -
ACS Infectious Diseases Jun 2024Vector-borne parasitic diseases (VBPDs) pose a significant threat to public health on a global scale. Collectively, Human African Trypanosomiasis (HAT), Leishmaniasis,...
Vector-borne parasitic diseases (VBPDs) pose a significant threat to public health on a global scale. Collectively, Human African Trypanosomiasis (HAT), Leishmaniasis, and Malaria threaten millions of people, particularly in developing countries. Climate change might alter the transmission and spread of VBPDs, leading to a global burden of these diseases. Thus, novel agents are urgently needed to expand therapeutic options and limit the spread of drug-resistant parasites. Herein, we report the development of broad-spectrum antiparasitic agents by screening a known library of antileishmanial and antimalarial compounds toward () and identifying a 1,3,4-oxadiazole derivative () as anti- hit with predicted blood-brain barrier permeability. Subsequently, extensive structure-activity-relationship studies around the lipophilic tail of led to a potent antitrypanosomal and antimalarial compound (), with moderate potency also toward () and . In addition, we discovered a pan-active antiparasitic molecule (), showing low-micromolar ICs toward and spp. promastigotes and amastigotes, and nanomolar IC against , together with high selectivity for the parasites over mammalian cells (THP-1). Early ADME-toxicity assays were used to assess the safety profile of the compounds. Overall, we characterized and , bearing the 1,3,4-oxadiazole privileged scaffold, as broad-spectrum low-toxicity agents for the treatment of VBPDs. An alkyne-substituted chemical probe () was synthesized and will be utilized in proteomics experiments aimed at deconvoluting the mechanism of action in the parasite.
Topics: Oxadiazoles; Trypanosoma brucei brucei; Humans; Structure-Activity Relationship; Drug Discovery; Antiparasitic Agents; Antimalarials; Leishmania infantum; Animals; Antiprotozoal Agents
PubMed: 38717116
DOI: 10.1021/acsinfecdis.4c00181 -
BioEssays : News and Reviews in... Jul 2024Trypanosoma brucei is the causal agent of African Trypanosomiasis in humans and other animals. It maintains a long-term infection through an antigenic variation based... (Review)
Review
Trypanosoma brucei is the causal agent of African Trypanosomiasis in humans and other animals. It maintains a long-term infection through an antigenic variation based population survival strategy. To proliferate in a mammal, T. brucei acquires iron and haem through the receptor mediated uptake of host transferrin and haptoglobin-hemoglobin respectively. The receptors are exposed to host antibodies but this does not lead to clearance of the infection. Here we discuss how the trypanosome avoids this fate in the context of recent findings on the structure and cell biology of the receptors.
Topics: Trypanosoma brucei brucei; Humans; Animals; Trypanosomiasis, African; Haptoglobins; Receptors, Cell Surface; Transferrin; Hemoglobins; Protozoan Proteins; Host-Parasite Interactions; Iron; Antibodies, Protozoan
PubMed: 38713161
DOI: 10.1002/bies.202400053