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Proceedings from the Fourth Mesoamerican Symposium "Dr. Roberto Navarro López" on Emerging Zoonotic Disease and Arboviruses: Commenting Insights and Research Findings.

Zoonotic pathogens such as arboviruses, arenaviruses, filoviruses, coronaviruses, highly pathogenic Avian Influenza A (H5N1) viruses, vesiculoviruses, and many others are emerging and reemerging worldwide, jeopardizing global veterinary and public health. Parasitic diseases such as visceral and cutaneous leishmaniasis, trypanosomiasis (Trypanosoma cruzi), myiasis, and river blindness (Onchocerca volvulus) are also paramount for public health in the Americas and elsewhere. In the fall 2024, a group of experts convened in Chiapas, Mexico, for the Fourth Mesoamerican Symposium "Dr. Roberto Navarr…

Exploration of innovative drug repurposing strategies for combating human protozoan diseases: Advances, challenges, and opportunities.

Protozoan infections (e.g., malaria, trypanosomiasis, and toxoplasmosis) pose a considerable global burden on public health and socioeconomic problems, leading to high rates of morbidity and mortality. Due to the limited arsenal of effective drugs for these diseases, which are associated with devastating side effects and escalating drug resistance, there is an urgent need for innovative antiprotozoal drugs. The emergence of drug repurposing offers a low-cost approach to discovering new therapies for protozoan diseases. In this review, we summarize recent advances in drug repurposing for variou…

Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei.

Trypanosoma brucei is a protozoan parasite that causes Human African Trypanosomiasis (HAT), a neglected tropical disease (NTD) that is endemic in 36 countries in sub-Saharan Africa. Only a handful drugs are available for treatment, and these have limitations, including toxicity and drug resistance. Using the natural product, curcumin, as a starting point, several curcuminoids and related analogs were evaluated against bloodstream forms of T. b. brucei. A particular subset of dibenzylideneacetone (DBA) compounds exhibited potent in vitro antitrypanosomal activity with sub-micromolar EC50 values…

Trypanosoma brucei proliferates normally even after losing all S-adenosylhomocysteine hydrolase genes.

S-adenosylhomocysteine (SAH) hydrolase is the enzyme responsible for breaking down SAH into adenosine and homocysteine. It has long been believed that a deficiency of this enzyme leads to SAH accumulation, subsequently inhibiting methyltransferases responsible for nucleic acids and proteins, which severely affects cell proliferation. To investigate whether targeting this enzyme could be a viable strategy to combat Trypanosoma brucei, the causative agent of human African trypanosomiasis, we created a null mutant of the SAH hydrolase gene in T. brucei using the Cre/loxP system and conducted a ph…

Transmigration of Trypanosoma brucei across an in vitro blood-cerebrospinal fluid barrier.

Trypanosoma brucei is the causative agent of human African trypanosomiasis. The parasite transmigrates from blood vessels across the choroid plexus epithelium to enter the central nervous system, a process that leads to the manifestation of second stage sleeping sickness. Using an in vitro model of the blood-cerebrospinal fluid barrier, we investigated the mechanism of the transmigration process. For this, a monolayer of human choroid plexus papilloma cells was cultivated on a permeable membrane that mimics the basal lamina underlying the choroid plexus epithelial cells. Plexus cells polarize …

Укрепление сбора данных о забытых тропических болезнях: Какие данные необходимы для того, чтобы модели могли лучше разрабатывать специальные программы вмешательства?

Все более важное значение для обеспечения достижения целей Всемирной организации здравоохранения (ВОЗ) в области борьбы с тропическими заболеваниями, которым не уделяется должного внимания на местном уровне, приобретают мероприятия по борьбе с ними. Математические модели, такие, как модели, разработанные Консорциумом по разработке моделей НТР, могут предлагать рекомендации в отношении мер вмешательства, но по-прежнему сдерживаются имеющимися в настоящее время данными. Необходимо активизировать сбор данных по НТР, поскольку для косвенной передачи информации в той или иной области требуются боле

Совпадение в аннотации оригинала
Locally tailored interventions for neglected tropical diseases (NTDs) are becoming increasingly important for ensuring that the World Health … n this collection, we discuss the data needs for several NTDs, specifically gambiense human African trypanosomiasis, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths (STH), trachoma, and visceral leishmaniasis. Similarities in the data needs for these NTDs highlight the potential for integration across these diseases and where pos …

mSphere of Influence: Expanding the CRISPR Sphere with Single-Locus Proteomics.

Lucy Glover's research focuses on the role of DNA repair and recombination in antigenic variation in the parasite Trypanosoma brucei, the causative agent of both human and animal African trypanosomiasis. In this mSphere of Influence article, she reflects on how "A CRISPR-based approach for proteomic analysis of a single genomic locus" by Z. J. Waldrip, S. D. Byrum, A. J. Storey, J. Gao, et al. (Epigenetics 9:1207-1211, 2014, https://doi.org/10.4161/epi.29919) made an impact on her research by taking the precision of CRISPR-Cas9 and repurposing it to look at single-locus proteomics. By using th…

Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine-Reductase-1 Inhibitors.

Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the … DHFR and PTR1 activity in T. brucei is a promising new strategy for the treatment of human African trypanosomiasis. For this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.

Discovery of Potent N-Ethylurea Pyrazole Derivatives as Dual Inhibitors of Trypanosoma brucei and Trypanosoma cruzi.

Trypanosoma brucei (T. brucei) and Trypanosoma cruzi (T. cruzi) are causative agents of parasitic diseases known as human African trypanosomiasis and Chagas disease, respectively. Together, these diseases affect 68 million people around the world. Current treatments are unsatisfactory, frequently associated with intolerable side-effects, and generally inadequate in treating all stages of disease. In this paper, we report the discovery of N-ethylurea pyrazoles that potently and selectively inhibit the viability of T. brucei and T. cruzi. Sharp and logical SAR led to the identification of 54 as …

Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.

Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( Ki < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalyt…

Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma.

The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure-based design. The best inhibitors were freely soluble and showed competitive inhibition constants (Ki ) against Trypanosoma (T.) brucei TR and T. cruzi TR and in vitro activities (half-…

Parasitic Diseases that can Infect Travelers to Africa.

Travel is important in the spread of diseases, and the number of travelers is increasing daily. Therefore, the importance of the diseases th … these travels, there is a risk of contracting parasitic diseases, such as malaria, schistosomiasis, trypanosomiasis (African sleeping disease), onchocerciasis, lymphatic filariasis, and leishmaniasis. Before traveling to Africa, it is vital to take measures against diseases in the region.

Drug Discovery for Kinetoplastid Diseases: Future Directions.

Kinetoplastid parasites have caused human disease for millennia. Significant achievements have been made toward developing new treatments for leishmaniasis (particularly on the Indian subcontinent) and for human African trypanosomiasis (HAT). Moreover, the sustained decrease in the incidence of HAT has made the prospect of elimination a tantalizing reality. Despite the gains, no new chemical or biological entities to treat kinetoplastid diseases have been registered in more than three decades, and more work is needed to discover safe and effective therapies for patients with Chagas disease and…

Synthesis and biological evaluation of selective tubulin inhibitors as anti-trypanosomal agents.

African trypanosomiasis is still a threat to human health due to the severe side-effects of current drugs. We identified selective tubulin inhibitors that showed the promise to the treatment of this disease, which was based on the tubulin protein structural difference between mammalian and trypanosome cells. Further lead optimization was performed in the current study to improve the efficiency of the drug candidates. We used Trypanosoma brucei brucei cells as the parasite model, and human normal kidney cells and mouse macrophage cells as the host model to evaluate the compounds. One new analog…

Novel triazine dimers with potent antitrypanosomal activity.

Human African trypanosomiasis (HAT), also known as sleeping sickness is a parasitic disease transmitted by the bite of the 'Glossina' insect, commonly known as the tsetse fly. This disease affects mostly poor populations living in remote rural areas of Africa. Untreated, it is usually fatal. Currently, safe and effective treatments against this disease are lacking. Phenotypic screening of triazine non-nucleoside HIV-1 reverse transcriptase inhibitors (monomers) resulted in potent and selective antitrypanosomal compounds. This serendipitous discovery and the presence of dimers in many compounds…

Selective inhibitors of trypanosomal uridylyl transferase RET1 establish druggability of RNA post-transcriptional modifications.

Non-coding RNAs are crucial regulators for a vast array of cellular processes and have been implicated in human disease. These biological pr … of this new target class as a therapeutic opportunity for the under-served disease area of African Trypanosomiasis. In a broader sense this work demonstrates the therapeutic potential for targeting RNA post-transcriptional modifications with small molecules in human disease.

Epigenetic Regulation of Virulence Gene Expression in Parasitic Protozoa.

Protozoan parasites colonize numerous metazoan hosts and insect vectors through their life cycles, with the need to respond quickly and reversibly while encountering diverse and often hostile ecological niches. To succeed, parasites must also persist within individuals until transmission between hosts is achieved. Several parasitic protozoa cause a huge burden of disease in humans and livestock, and here we focus on the parasites that cause malaria and African trypanosomiasis. Efforts to understand how these pathogens adapt to survive in varied host environments, cause disease, and transmit be…

Oxa, Thia, Heterocycle, and Carborane Analogues of SQ109: Bacterial and Protozoal Cell Growth Inhibitors.

We synthesized a library of 48 analogs of the Mycobacterium tuberculosis cell growth inhibitor SQ109 in which the ethylene diamine linker wa … oma, HepG2). Most potent activity was found against T. brucei, the causative agent of human African trypanosomiasis, and involved targeting of the mitochondrial membrane potential with 15 SQ109 analogs being more active than was SQ109 in cell growth inhibition, having IC50 values as low as 12 nM (5.5 ng/mL) and a selectivity index of ~300.

Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors.

Neglected tropical diseases remain a serious global health concern. Here, a series of novel bis-tetrahydropyran 1,4-triazole analogues based on the framework of chamuvarinin, a polyketide natural product isolated from the annonaceae plant species are detailed. The analogues synthesized display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness, also known as Human African Trypanosomiasis (HAT). A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediate…

Repurposing human PDE4 inhibitors for neglected tropical diseases. Evaluation of analogs of the human PDE4 inhibitor GSK-256066 as inhibitors of PDEB1 of Trypanosoma brucei.

Cyclic nucleotide phosphodiesterases (PDEs) have been identified as important enzyme targets for drug development in both humans and Trypanosoma brucei, the causative agent of human African trypanosomiasis. With this in mind, we recently reported the profiling of a range of human phosphodiesterase inhibitors, showing that human PDE4 inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK-256066, a potent inhibitor of human PDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure-activity relations…