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Annual Review of Pathology Jan 2023African trypanosomes are bloodstream protozoan parasites that infect mammals including humans, where they cause sleeping sickness. Long-lasting infection is required to... (Review)
Review
African trypanosomes are bloodstream protozoan parasites that infect mammals including humans, where they cause sleeping sickness. Long-lasting infection is required to favor parasite transmission between hosts. Therefore, trypanosomes have developed strategies to continuously escape innate and adaptive responses of the immune system, while also preventing premature death of the host. The pathology linked to infection mainly results from inflammation and includes anemia and brain dysfunction in addition to loss of specificity and memory of the antibody response. The serum of humans contains an efficient trypanolytic factor, the membrane pore-forming protein apolipoprotein L1 (APOL1). In the two human-infective trypanosomes, specific parasite resistance factors inhibit APOL1 activity. In turn, many African individuals express APOL1 variants that counteract these resistance factors, enabling them to avoid sleeping sickness. However, these variants are associated with chronic kidney disease, particularly in the context of virus-induced inflammation such as coronavirus disease 2019. Vaccination perspectives are discussed.
Topics: Humans; Apolipoprotein L1; COVID-19; Inflammation; Trypanosoma brucei rhodesiense; Trypanosomiasis, African
PubMed: 36055769
DOI: 10.1146/annurev-pathmechdis-031621-025153 -
Science (New York, N.Y.) Jun 2023Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT)....
Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT. Cryo-electron microscopy approaches confirmed that CT compounds acted through selective, irreversible inhibition of trypanosomal topoisomerase II by stabilizing double-stranded DNA:enzyme cleavage complexes. These findings suggest a potential approach toward successful therapeutics for the treatment of Chagas disease.
Topics: Animals; Humans; Mice; Chagas Disease; Cryoelectron Microscopy; DNA Topoisomerases, Type II; Trypanosoma; Topoisomerase II Inhibitors; Triazoles; Trypanosomiasis, African; Drug Evaluation, Preclinical
PubMed: 37384702
DOI: 10.1126/science.adh0614 -
Antimicrobial Agents and Chemotherapy Feb 2020Suramin is 100 years old and is still being used to treat the first stage of acute human sleeping sickness, caused by Suramin is a multifunctional molecule with a wide... (Review)
Review
Suramin is 100 years old and is still being used to treat the first stage of acute human sleeping sickness, caused by Suramin is a multifunctional molecule with a wide array of potential applications, from parasitic and viral diseases to cancer, snakebite, and autism. Suramin is also an enigmatic molecule: What are its targets? How does it get into cells in the first place? Here, we provide an overview of the many different candidate targets of suramin and discuss its modes of action and routes of cellular uptake. We reason that, once the polypharmacology of suramin is understood at the molecular level, new, more specific, and less toxic molecules can be identified for the numerous potential applications of suramin.
Topics: Animals; Humans; Suramin; Trypanocidal Agents; Trypanosoma brucei rhodesiense; Trypanosomiasis, African
PubMed: 31844000
DOI: 10.1128/AAC.01168-19 -
Molecules (Basel, Switzerland) Oct 2020Trypanosomiases are diseases caused by parasitic protozoan trypanosomes of the genus . In humans, this includes Chagas disease and African trypanosomiasis. There are few... (Review)
Review
Trypanosomiases are diseases caused by parasitic protozoan trypanosomes of the genus . In humans, this includes Chagas disease and African trypanosomiasis. There are few therapeutic options, and there is low efficacy to clinical treatment. Therefore, the search for new drugs for the trypanosomiasis is urgent. This review describes studies of the trypanocidal properties of essential oils, an important group of natural products widely found in several tropical countries. Seventy-seven plants were selected from literature for the trypanocidal activity of their essential oils. The main chemical constituents and mechanisms of action are also discussed. In vitro and in vivo experimental data show the therapeutic potential of these natural products for the treatment of infections caused by species of .
Topics: Animals; Chagas Disease; Humans; Oils, Volatile; Plant Extracts; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosoma cruzi; Trypanosomiasis, African
PubMed: 33036315
DOI: 10.3390/molecules25194568 -
Molecules (Basel, Switzerland) Nov 2020Discovering and validating effective drugs to manage arthropod-borne diseases (ABD) is a timely and important research challenge with major impacts on real-world control...
Discovering and validating effective drugs to manage arthropod-borne diseases (ABD) is a timely and important research challenge with major impacts on real-world control programs at the time of quick resistance development in the targeted pathogens. This editorial highlights major research advances in the development of drugs for the control of vector-borne diseases, with a significant focus on malaria, Chagas disease, dengue, human African trypanosomiasis, leishmaniasis, and Zika. Broad reviews providing new insights on ABD recently published in have also been covered in "The Editors' pick" section.
Topics: Animals; Antimalarials; Antiviral Agents; Arthropod Vectors; Dengue; Drug Development; Humans; Leishmaniasis; Malaria, Falciparum; Trypanocidal Agents; Zika Virus Infection
PubMed: 33172077
DOI: 10.3390/molecules25215175 -
Tropical Medicine and Infectious Disease Apr 2020Human African trypanosomiasis (HAT; sleeping sickness) is a disease with truly historic dimensions [...].
Human African trypanosomiasis (HAT; sleeping sickness) is a disease with truly historic dimensions [...].
PubMed: 32276514
DOI: 10.3390/tropicalmed5020057 -
Microorganisms Jun 2022Human African Trypanosomiasis (HAT, sleeping sickness) and Animal African Trypanosomiasis (AAT) are neglected tropical diseases generally caused by the same etiological... (Review)
Review
Human African Trypanosomiasis (HAT, sleeping sickness) and Animal African Trypanosomiasis (AAT) are neglected tropical diseases generally caused by the same etiological agent, . Despite important advances in the reduction or disappearance of HAT cases, AAT represents a risky reservoir of the infections. There is a strong need to control AAT, as is claimed by the European Commission in a recent document on the reservation of antimicrobials for human use. Control of AAT is considered part of the One Health approach established by the FAO program against African Trypanosomiasis. Under the umbrella of the One Health concepts, in this work, by analyzing the pharmacological properties of the therapeutic options against spp., we underline the need for clearer and more defined guidelines in the employment of drugs designed for HAT and AAT. Essential requirements are addressed to meet the challenge of drug use and drug resistance development. This approach shall avoid inter-species cross-resistance phenomena and retain drugs therapeutic activity.
PubMed: 35889018
DOI: 10.3390/microorganisms10071298 -
Nature Reviews. Microbiology Jan 2023Leishmaniasis (visceral and cutaneous), Chagas disease and human African trypanosomiasis cause substantial death and morbidity, particularly in low- and middle-income... (Review)
Review
Leishmaniasis (visceral and cutaneous), Chagas disease and human African trypanosomiasis cause substantial death and morbidity, particularly in low- and middle-income countries. Although the situation has improved for human African trypanosomiasis, there remains an urgent need for new medicines to treat leishmaniasis and Chagas disease; the clinical development pipeline is particularly sparse for Chagas disease. In this Review, we describe recent advances in our understanding of the biology of the causative pathogens, particularly from the drug discovery perspective, and we explore the progress that has been made in the development of new drug candidates and the identification of promising molecular targets. We also explore the challenges in developing new clinical candidates and discuss potential solutions to overcome such hurdles.
Topics: Animals; Humans; Trypanosomiasis, African; Chagas Disease; Leishmaniasis; Drug Discovery
PubMed: 35995950
DOI: 10.1038/s41579-022-00777-y