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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 -
Pathogens (Basel, Switzerland) Oct 2023Human African trypanosomiasis (also known as sleeping sickness, with and as etiological agents), American trypanosomiasis (also known as Chagas disease, with as the...
Human African trypanosomiasis (also known as sleeping sickness, with and as etiological agents), American trypanosomiasis (also known as Chagas disease, with as the etiological agent), and leishmaniasis (including cutaneous, mucocutaneous, and visceral forms, with multiple species belonging to the genus as etiological agents) are recognized as neglected tropical diseases (NTDs) [...].
PubMed: 37887779
DOI: 10.3390/pathogens12101263 -
Developmental Medicine and Child... Apr 2024Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia. The... (Review)
Review
Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia. The condition is caused by 3'-end mutations of the ornithine decarboxylase 1 (ODC1) gene, which produce carboxy (C)-terminally truncated variants of ODC, a pyridoxal 5'-phosphate-dependent enzyme. C-terminal truncation of ODC prevents its ubiquitin-independent proteasomal degradation and leads to cellular accumulation of ODC enzyme that remains catalytically active. ODC is the first rate-limiting enzyme that converts ornithine to putrescine in the polyamine pathway. Polyamines (putrescine, spermidine, spermine) are aliphatic molecules found in all forms of life and are important during embryogenesis, organogenesis, and tumorigenesis. BABS is an ultra-rare condition with few reported cases, but it serves as a convincing example for drug repurposing therapy. α-Difluoromethylornithine (DFMO, also known as eflornithine) is an ODC inhibitor with a strong safety profile in pediatric use for neuroblastoma and other cancers as well as West African sleeping sickness (trypanosomiasis). Patients with BABS have been treated with DFMO and have shown improvement in hair growth, muscle tone, and development.
Topics: Humans; Child; Putrescine; Spermidine; Polyamines; Spermine; Eflornithine
PubMed: 37469105
DOI: 10.1111/dmcn.15687 -
International Journal of Molecular... Aug 2023Human African trypanosomiasis is a neglected tropical disease caused by the extracellular protozoan parasite , and targeted for eradication by 2030. The COVID-19... (Review)
Review
Human African trypanosomiasis is a neglected tropical disease caused by the extracellular protozoan parasite , 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.
Topics: Animals; Humans; Trypanosomiasis, African; Pandemics; COVID-19; Trypanosoma brucei brucei; Trypanosoma
PubMed: 37569903
DOI: 10.3390/ijms241512529 -
Virulence Dec 2023African trypanosomes are vector-borne protozoa, which cause significant human and animal disease across sub-Saharan Africa, and animal disease across Asia and South... (Review)
Review
African trypanosomes are vector-borne protozoa, which cause significant human and animal disease across sub-Saharan Africa, and animal disease across Asia and South America. In humans, infection is caused by variants of , and is characterized by varying rate of progression to neurological disease, caused by parasites exiting the vasculature and entering the brain. Animal disease is caused by multiple species of trypanosome, primarily , and . These trypanosomes also infect multiple species of mammalian host, and this complexity of trypanosome and host diversity is reflected in the spectrum of severity of disease in animal trypanosomiasis, ranging from hyperacute infections associated with mortality to long-term chronic infections, and is also a main reason why designing interventions for animal trypanosomiasis is so challenging. In this review, we will provide an overview of the current understanding of trypanosome determinants of infection progression and severity, covering laboratory models of disease, as well as human and livestock disease. We will also highlight gaps in knowledge and capabilities, which represent opportunities to both further our fundamental understanding of how trypanosomes cause disease, as well as facilitating the development of the novel interventions that are so badly needed to reduce the burden of disease caused by these important pathogens.
Topics: Animals; Humans; Trypanosomiasis, African; Virulence; Tsetse Flies; Trypanosoma; Trypanosomiasis; Mammals
PubMed: 36419235
DOI: 10.1080/21505594.2022.2150445 -
Trends in Parasitology Dec 2023African trypanosomes show a remarkable ability to survive as extracellular parasites in the blood and tissue spaces of an infected mammal. Throughout the infection they... (Review)
Review
African trypanosomes show a remarkable ability to survive as extracellular parasites in the blood and tissue spaces of an infected mammal. Throughout the infection they are exposed to the molecules and cells of the immune system, including complement. In this opinion piece, we review decades-worth of evidence about how complement affects African trypanosomes. We highlight the discovery of a trypanosome receptor for complement C3 and we critically assess three recent studies which attempt to provide a structural and mechanistic view of how this receptor helps trypanosomes to survive in the presence of complement.
Topics: Animals; Trypanosoma; Trypanosomiasis, African; Mammals
PubMed: 37758633
DOI: 10.1016/j.pt.2023.09.001 -
Nature Microbiology Nov 2023Trypanosoma brucei causes African trypanosomiasis, colonizing adipose tissue and inducing weight loss. Here we investigated the molecular mechanisms responsible for...
Trypanosoma brucei causes African trypanosomiasis, colonizing adipose tissue and inducing weight loss. Here we investigated the molecular mechanisms responsible for adipose mass loss and its impact on disease pathology. We found that lipolysis is activated early in infection. Mice lacking B and T lymphocytes fail to upregulate adipocyte lipolysis, resulting in higher fat mass retention. Genetic ablation of the rate-limiting adipose triglyceride lipase specifically from adipocytes (Adipoq-Atgl) prevented the stimulation of adipocyte lipolysis during infection, reducing fat mass loss. Surprisingly, these mice succumbed earlier and presented a higher parasite burden in the gonadal adipose tissue, indicating that host lipolysis limits parasite growth. Consistently, free fatty acids comparable with those of adipose interstitial fluid induced loss of parasite viability. Adipocyte lipolysis emerges as a mechanism controlling local parasite burden and affecting the loss of fat mass in African trypanosomiasis.
Topics: Animals; Mice; Lipolysis; Trypanosoma brucei brucei; Trypanosomiasis, African; Lipase; Adipocytes; Obesity
PubMed: 37828246
DOI: 10.1038/s41564-023-01496-7