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Journal of Medicinal Chemistry Mar 2024Human African trypanosomiasis (HAT), a neglected tropical disease caused by () or (), remains a significant public health concern with over 55 million people at risk...
Human African trypanosomiasis (HAT), a neglected tropical disease caused by () or (), remains a significant public health concern with over 55 million people at risk of infection. Current treatments for HAT face the challenges of poor efficacy, drug resistance, and toxicity. This study presents the synthesis and evaluation of chloronitrobenzamides (CNBs) against , identifying previously reported compound as a potent and selective orally bioavailable antitrypanosomal agent. was well tolerated in vivo and demonstrated favorable oral pharmacokinetics, maintaining plasma concentrations surpassing the cellular EC for over 24 h and achieving peak brain concentrations exceeding 7 μM in rodents after single oral administration (50 mg/kg). Treatment with significantly extended the lifespan of mice infected with and . These results demonstrate that is a strong antitrypanosomal lead with potential for developing treatments for both human and animal African trypanosomiasis.
Topics: Humans; Animals; Mice; Trypanosomiasis, African; Trypanosoma brucei rhodesiense; Trypanosoma brucei gambiense; Trypanosoma brucei brucei; Trypanocidal Agents
PubMed: 38363074
DOI: 10.1021/acs.jmedchem.3c01680 -
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 -
Current Tropical Medicine Reports Dec 2023Human African Trypanosomiasis (HAT), also known as sleeping sickness, is a vector-borne parasitic neglected tropical disease (NTD) endemic in sub-Saharan Africa. This...
PURPOSE OF REVIEW
Human African Trypanosomiasis (HAT), also known as sleeping sickness, is a vector-borne parasitic neglected tropical disease (NTD) endemic in sub-Saharan Africa. This review aims to enhance our understanding of HAT and provide valuable insights to combat this significant public health issue by synthesizing the latest research and evidence.
RECENT FINDINGS
HAT has reached a historical < 1000 cases in 2018. In patients without neurologic symptoms and signs, the likelihood of a severe meningoencephalitic stage is deemed low, obviating the need for a lumbar puncture to guide treatment decisions using fexinidazole.
SUMMARY
Both forms of the disease, gambiense HAT (gHAT) and rhodesiense HAT (rHAT), have specific epidemiology, risk factors, diagnosis, and treatment. Disease management still requires a high index of suspicion, infectious disease expertise, and specialized medical care. Essential stakeholders in health policy are critical to accomplishing the elimination goals of the NTD roadmap for 2021-2030.
PubMed: 38939748
DOI: 10.1007/s40475-023-00304-w -
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 -
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 -
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