Article
Biochemistry & Molecular Biology
Roberto Docampo, Anibal Eugenio Vercesi
Summary: This review discusses the mechanisms of mitochondrial oxidant generation and removal, and the involvement of Ca2+ in trypanosome cell death, highlighting the need for further studies on ROS generation, defense mechanisms, and mitochondrial permeability transition pore in trypanosomatids.
ANTIOXIDANTS & REDOX SIGNALING
(2022)
Review
Pharmacology & Pharmacy
Aline A. Zuma, Emile dos Santos Barrias, Wanderley de Souza
Summary: This review discusses the basic biology of the pathogenic protozoa Trypanosoma cruzi and Trypanosoma brucei, highlighting their developmental stages and unique structural characteristics, which can potentially serve as chemotherapeutic targets. Understanding these aspects contributes to drug development for chemotherapy.
CURRENT PHARMACEUTICAL DESIGN
(2021)
Article
Chemistry, Medicinal
Yang Zheng, Magali van den Kerkhof, Tiffany van der Meer, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Iwan J. P. de Esch, Marco Siderius, An Matheeussen, Louis Maes, Geert Jan Sterk, Guy Caljon, Rob Leurs
Summary: The discovery of 5-phenylpyrazolopyrimidinone analogs as a novel series of antitrypanosomal agents shows promise for developing new medications to treat Human African Trypanosomiasis (HAT). The most potent compound, 30, has a low toxicity potential and exhibits high in vitro and in vivo antitrypanosomal activity against T. b. brucei.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Microbiology
Nuria W. Negrao, Logan P. Crowe, Brian S. Mantilla, Rodrigo P. Baptista, Sharon King-Keller, Guozhong Huang, Roberto Docampo
Summary: Trypanosoma brucei is the causative agent of African trypanosomiasis, and there is a need for new drugs due to limited treatment options and evidence of resistance. A phosphoinositide phospholipase C (TbPI-PLC-like) with an X and PDZ domain was discovered, similar to TbPI-PLC1. Recombinant TbPI-PLC-like does not hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) and does not modulate TbPI-PLC1 activity, but its knockdown affects the proliferation of trypanosomes.
Article
Microbiology
Joseph T. Smith Jr, Brianna Tylec, Arunasalam Naguleswaran, Isabel Roditi, Laurie K. Read
Summary: This study reveals the importance of mitochondrial mRNA editing in the developmental regulation of Trypanosoma brucei. The researchers found that temperature reduction and depletion of the differentiation-repressive kinase RDK1 can affect the metabolism of Trypanosoma brucei by altering the editing of mitochondrial cytochrome mRNAs.
Article
Chemistry, Medicinal
Sabina Beilstein, Radhia El Phil, Suzanne Sherihan Sahraoui, Leonardo Scapozza, Marcel Kaiser, Pascal Maser
Summary: This article discusses the experimental methods and strategies for selecting drug-resistant parasites, using African trypanosomes as an example. Researchers need to consider factors such as the environmental conditions, life stages, and pressure for selecting drug resistance, while taking into account the laboratory settings.
Article
Biochemistry & Molecular Biology
Cecilia Ortiz, Francesca Moraca, Marc Laverriere, Allan Jordan, Niall Hamilton, Marcelo A. Comini
Summary: G6PDH plays a crucial role in cell physiology by catalyzing the synthesis of NADPH(+) and ribose 5-phosphate. The study discovered that 16 alpha-brominated epiandrosterone is the most potent inhibitor of G6PDH in trypanosomatids. Further investigations showed that bromination at position 16 alpha of androstane derivatives yielded more potent T. cruzi G6PDH inhibitors.
Article
Biochemistry & Molecular Biology
Kyung-Hwa Baek, Trong-Nhat Phan, Satish R. Malwal, Hyeryon Lee, Zhu-Hong Li, Silvia N. J. Moreno, Eric Oldfield, Joo Hwan No
Summary: SQ109 is an anti-tubercular drug candidate that has shown potent activity against protozoan parasites including Leishmania, Trypanosoma cruzi, and Toxoplasma gondii in vitro. It has demonstrated efficacy in mouse models of T. cruzi and T. gondii infections, but moderate efficacy in models of Trypanosoma brucei and Leishmania donovani infections. Metabolites of SQ109 also exhibit activity against protozoan parasites in vitro.
Article
Biochemistry & Molecular Biology
George E. Magoulas, Pantelis Afroudakis, Kalliopi Georgikopoulou, Marina Roussaki, Chiara Borsari, Theano Fotopoulou, Nuno Santarem, Emile Barrias, Paloma Tejera Nevado, Julia Hachenberg, Eugenia Bifeld, Bernhard Ellinger, Maria Kuzikov, Irini Fragiadaki, Effie Scoulica, Joachim Clos, Sheraz Gul, Maria Paola Costi, Wanderley de Souza, Kyriakos C. Prousis, Anabela Cordeiro da Silva, Theodora Calogeropoulou
Summary: A library of novel ether phospholipid analogues was designed and synthesized, with compounds showing potent antiparasitic activity against different parasitic species. The structure-activity relationships of these compounds were studied, and a potential lead compound with broad spectrum antiparasitic activity was identified, laying a foundation for the development of improved derivatives to control neglected tropical diseases.
Article
Parasitology
Catherine N. Mutuku, Rosemary Bateta, Martin K. Rono, James M. Njunge, Erick O. Awuoche, Kariuki Ndung'u, Clarence M. Mang'era, Modesta O. Akoth, Vincent O. Adung'a, Bartholomew N. Ondigo, Paul O. Mireji
Summary: This study assessed suramin response, drug resistance, and pathogenicity of Tbr parasite strains isolated from HAT patients in Uganda, revealing potential mechanisms of suramin treatment failure and resistance in Tbr parasites.
INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
(2021)
Article
Immunology
Laura Fraccaroli, Maria Daniela Ruiz, Virginia Gabriela Perdomo, Agustina Nicole Clausi, Dario Emmanuel Balcazar, Luciana Larocca, Carolina Carrillo
Summary: "Chagas disease is an endemic American parasitosis caused by Trypanosoma cruzi. Current therapies have limited efficacy and side effects, leading to the need for new trypanocidal strategies. Ivermectin shows potential as a repurposed drug for Chagas disease, with dose-dependent effects on T. cruzi and other trypanosomatids, and potential novel molecular targets identified in this study."
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Infectious Diseases
Arunima Goswami, Tirthankar Koley, Madhan Vishal Rajan, Pathak Madhuri, Neelam Upadhyay, Uddipan Das, Manoj Kumar, Abdul Samath Ethayathulla, Gururao Hariprasad
Summary: This study found that Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, which are protozoan parasites, cause leishmaniasis, Chagas disease, and sleeping sickness, respectively. It was found that PAF-AH is an inflammatory protein involved in the pathogenesis of these three infections, making it an attractive drug target.
INFECTION AND DRUG RESISTANCE
(2023)
Article
Biochemistry & Molecular Biology
Sinclair Cooper, Elizabeth S. Wadsworth, Achim Schnaufer, Nicholas J. Savill
Summary: The mitochondrial DNA of protists of order Kinetoplastida consists of thousands of interlinked circular molecules. It includes two types of molecules, minicircles and maxicircles. Minicircles encode guide RNA (gRNA) genes that mediate post-transcriptional editing of maxicircle encoded genes. The human sleeping sickness parasite Trypanosoma brucei has a diverse set of minicircle classes, some of which contain decaying remnants of once functional gRNA genes. The sequencing and annotation of minicircle classes in T. brucei subspecies and isolates have provided valuable data for understanding their structure and transcription.
Article
Immunology
Julian Ernesto Nicolas Gulin, Margarita Maria Catalina Bisio, Daniela Rocco, Jaime Altcheh, Maria Elisa Solana, Facundo Garcia-Bournissen
Summary: This study evaluates the efficacy of Miltefosine (MLT) as a monodrug and combined with benznidazole (BZ) for treating Trypanosoma cruzi infection. MLT showed promising results in inhibiting the parasite in both in vitro and in vivo models, with improved efficacy when combined with BZ. This study provides support for the potential use of MLT in Chagas disease treatment and the exploration of combination therapies.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Biology
Lorraine Martins Rocha Orlando, Leonardo da Silva Lara, Guilherme Curty Lechuga, Giseli Capaci Rodrigues, Omar Ginoble Pandoli, Druval Santos de Sa, Mirian Claudia de Souza Pereira
Summary: Therapeutic alternatives for Chagas disease are urgently needed due to limitations and adverse effects of current drugs. Triazole analogues show promise in treating T. cruzi.
Article
Microbiology
Joana Faria, Vanessa Luzak, Laura S. M. Muller, Benedikt G. Brink, Sebastian Hutchinson, Lucy Glover, David Horn, T. Nicolai Siegel
Summary: The study reveals a mechanism in Trypanosoma brucei where a single expressed antigen-coding gene interacts with a major messenger RNA splicing locus in a specific nuclear compartment, ensuring monogenic expression. Specific proteins VEX1 and VEX2 are associated with an antigen exclusion complex, playing a role in this process of antigen transcription and mRNA splicing. Depletion of VEX2 results in loss of monogenic antigen expression and increased interactions between previously silent antigen genes and the splicing locus.
NATURE MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Carys Davies, Cher-Pheng Ooi, Georgios Sioutas, Belinda S. Hall, Haneesh Sidhu, Falk Butter, Sam Alsford, Bill Wickstead, Gloria Rudenko
Summary: The African trypanosome Trypanosoma brucei relies on a protective VSG coat for survival in mammalian hosts. A whole genome RNAi library screen identified a novel DNA binding protein TbSAP, which plays an important role in silencing the extensive VSG repertoire in bloodstream form T. brucei.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Multidisciplinary Sciences
N. Baker, C. M. C. Catta-Preta, R. Neish, J. Sadlova, B. Powell, E. V. C. Alves-Ferreira, V. Geoghegan, J. B. T. Carnielli, K. Newling, C. Hughes, B. Vojtkova, J. Anand, A. Mihut, P. B. Walrad, L. G. Wilson, J. W. Pitchford, P. Volf, J. C. Mottram
Summary: This study identified important protein kinase genes in Leishmania mexicana that are involved in transition between different life cycle stages, as well as revealed their functions in parasitism in macrophages, colonization of the sand fly, and motility.
NATURE COMMUNICATIONS
(2021)
Review
Parasitology
David Horn
Summary: Genome-scale genetic screens have played a crucial role in African trypanosomes by uncovering mechanisms related to drug resistance, metabolism, and gene expression control. They have also been effective in identifying potential antitrypanosomal drug targets.
TRENDS IN PARASITOLOGY
(2022)
Article
Multidisciplinary Sciences
Yanika Borg, Sam Alsford, Vasos Pavlika, Alexei Zaikin, Darren N. Nesbeth
Summary: Kinetoplastid protozoa, with unique properties, have been shown to hold bioengineering potential. This study successfully constructed an oscillatory gene network in Trypanosoma brucei for the first time, laying the foundation for future synthetic biology research.
Article
Chemistry, Medicinal
Alasdair Smith, Richard J. Wall, Stephen Patterson, Tim Rowan, Eva Rico Vidal, Laste Stojanovski, Margaret Huggett, Shahienaz E. Hampton, Michael G. Thomas, Victoriano Corpas Lopez, Kirsten Gillingwater, Jeff Duke, Grant Napier, Rose Peter, Herve S. Vitouley, Justin R. Harrison, Rachel Milne, Laura Jeacock, Nicola Baker, Susan H. Davis, Frederick Simeons, Jennifer Riley, David Horn, Reto Brun, Fabio Zuccotto, Michael J. Witty, Susan Wyllie, Kevin D. Read, Ian H. Gilbert
Summary: African animal trypanosomiasis is a major problem in cattle and other livestocks in sub-Saharan Africa and current treatments are facing drug resistance. A medicinal chemistry program has developed a lead compound capable of curing cattle infected with two types of trypanosomes via intravenous dosing, with potential for further optimization to provide a single-dose intramuscular treatment for this disease.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Simone Altmann, Eva Rico, Sandra Carvalho, Melanie Ridgway, Anna Trenaman, Hannah Donnelly, Michele Tinti, Susan Wyllie, David Horn
Summary: This study reports a simple method for rapid and precise editing of priority drug targets in trypanosomatids. By targeting and editing drug targets, combined with sequencing technology, potential impacts on drug efficacy can be assessed quickly.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Microbiology
Gustavo Bravo Ruiz, Michele Tinti, Melanie Ridgway, David Horn
Summary: VSG expression plays a crucial role in parasite virulence and is a fascinating subject in extreme biology. This study identified three candidate VSG regulators and demonstrated the role of CFB2 in controlling VSG expression through the VSG 3' UTR. Additionally, insights into the connections between VSG expression control, ribosomal protein expression, and cytokinesis were revealed.
Correction
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
NATURE REVIEWS MICROBIOLOGY
(2022)
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are major causes of death and illness, particularly in low- and middle-income countries. The development of new medicines for leishmaniasis and Chagas disease is urgently needed, with limited progress in the clinical pipeline for Chagas disease. This review provides an overview of recent advances in understanding the biology of these pathogens, with a focus on drug discovery, as well as the development of new drug candidates and potential solutions to overcome challenges in clinical development.
NATURE REVIEWS MICROBIOLOGY
(2023)
Article
Multidisciplinary Sciences
Catarina A. Marques, Melanie Ridgway, Michele Tinti, Andrew Cassidy, David Horn
Summary: In this study, a genome-wide RNA-interference library screen was used to investigate the cell cycle defects in Trypanosoma brucei. The results provide comprehensive functional genomic evidence for the known and novel machineries, pathways, and regulators that coordinate trypanosome cell cycle progression.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Livio Racane, Lucija Pticek, Sanja Kostrun, Silvana Raic-Malic, Martin Craig Taylor, Michael Delves, Sam Alsford, Francisco Olmo, Amanda Fortes Francisco, John M. Kelly
Summary: We designed and synthesized a series of symmetric benzothiazole derivatives and evaluated their efficacy against Trypanosoma brucei and Plasmodium falciparum. One compound showed high selectivity and trypanocidal activity, curing mice infected with trypanosomiasis. It also exhibited activity against the malaria parasite.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Microbiology
Douglas Escrivani, Viktor Scheidt, Michele Tinti, Joana Faria, David Horn
Summary: Some pathogens use antigenic variation to evade mammalian host adaptive immune responses. African trypanosomes employ variant surface glycoproteins (VSGs) to continually switch their active VSGs and avoid immune recognition. Switched trypanosomes compete in a predictable manner that is dependent on the activated VSG, and the population of cells that activates minichromosome derived VSGs has a competitive advantage.
Article
Microbiology
Anna Trenaman, Michele Tinti, Abdelmadjid Atrih, David Horn
Summary: Nucleoside analogs are widely used as anti-infective agents, but their potential as anti-parasitic agents has not been fully explored. This study identified two proteins, Tb927.6.2800 and HD82, associated with purine analog resistance in African trypanosomes. The findings also validated two nucleoside kinases involved in pro-drug activation. HD82, related to the mammalian nuclear viral restriction factor SAMHD1, sensitized trypanosomes to nucleoside analogs by reducing native nucleotide pools. This study provides insights into nucleoside/nucleotide metabolism and nucleoside analog resistance in trypanosomatids.
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are causing significant death and morbidity, especially in low- and middle-income countries. There is a critical need for new medications for leishmaniasis and Chagas disease, while the clinical development pipeline for Chagas disease remains sparse. This review discusses recent advancements in understanding the biology of these pathogens, with a focus on drug discovery, and explores progress in developing new drug candidates and identifying potential molecular targets. The challenges in developing new clinical candidates are also discussed, along with potential solutions to overcome these hurdles.
NATURE REVIEWS MICROBIOLOGY
(2023)