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Rachel B Currier, Anneli Cooper, Hollie Burrell-Saward, Annette MacLeod, Sam Alsford
In contrast to Trypanosoma brucei gambiense and T. b. rhodesiense (the causative agents of human African trypanosomiasis), T. b. brucei is lysed by apolipoprotein-L1 (apoL1)-containing human serum trypanolytic factors (TLF), rendering it non-infectious to humans. While the mechanisms of TLF1 uptake, apoL1 membrane integration, and T. b. gambiense and T. b. rhodesiense apoL1-resistance have been extensively characterised, our understanding of the range of factors that drive apoL1 action in T. b. brucei is limited...
January 18, 2018: PLoS Pathogens
Andrea Gloria-Soria, W Augustine Dunn, Xiaoqing Yu, Aurélien Vigneron, Kuang-Yao Lee, Mo Li, Brian L Weiss, Hongyu Zhao, Serap Aksoy, Adalgisa Caccone
Vector-borne diseases are responsible for more than one million deaths every year but genomic resources for most species responsible for their transmission are limited. This is true for neglected diseases such as sleeping sickness (Human African Trypanosomiasis), a disease caused by Trypanosoma parasites vectored by several species of tseste flies within the genus Glossina We describe an integrative approach that identifies statistical associations between trypanosome infection status of Glossina fuscipes fuscipes (Gff) flies from Uganda, for which functional studies are complicated because the species cannot be easily maintained in laboratory colonies, and ~73,000 polymorphic sites distributed across the genome...
January 17, 2018: G3: Genes—Genomes—Genetics
Qunbo Tong, Rui Chen, Qingming Kong, Julie Goossens, Magdalena Radwanska, Di Lou, Jianzu Ding, Bin Zheng, Yixiu Fu, Tianping Wang, Magez Stefan, Shaohong Lu
Trypanosoma evansi (T. evansi) is the most widely spread pathogenic trypanosome in the world. The control of trypanosomiasis depends on accurate diagnosis and effective treatment. Focusing on the presence of T. evansi in Asia, we developed a detection assay based on tracing phosphate ions (Pi) generated during LAMP targeting the variant surface glycoprotein (VSG) gene of Rode Trypanozoon antigenic type 1.2 (RoTat 1.2 VSG). The diagnostic potential as well as the use of the assay as a test-of-cure method after berenil treatment, was assessed in mice at different time points of infection...
January 30, 2018: Veterinary Parasitology
Maurice Grube, Lee Bo-Young, Monika Garg, Dana Michel, Ankita Malik, Ivan Vilotijevic, Peter H Seeberger, Daniel Varon Silva
Trypanosoma brucei uses variant surface glycoproteins (VSGs) to evade the host immune system and ensure parasitic longevity in animals and humans. VSGs are attached to the cell membrane by complex glycosylphosphatidylinositol anchors (GPI). Distinguishing structural feature of VSG GPIs are multiple alpha and beta-galactosides attached to the conserved GPI core structure. T. brucei GPIs have been associated with macrophage activation and alleviation of parasitemia during infection, acting as disease onset delaying antigens...
January 3, 2018: Chemistry: a European Journal
Edson Santos Dantas, Rodrigo Gurgel-Gonçalves, Daniel Antunes Maciel Villela, Fernando Araújo Monteiro, Rafael Maciel-de-Freitas
BACKGROUND: Chagas disease, or American trypanosomiasis, is an important neglected tropical illness caused by the flagellate protozoan Trypanosoma cruzi, which is primarily transmitted to humans by hematophagous insects of the subfamily Triatominae. Although knowledge on triatomine movement capabilities at the micro-geographical scale is of fundamental importance concerning the development of effective vector control strategies, it remains a poorly understood subject. Furthermore, survival rates and size estimates of natural populations are important topics to consider when evaluating transmission intensity...
January 5, 2018: Parasites & Vectors
Naimee Mehta, Lori Ferrins, Susan E Leed, Richard J Sciotti, Michael P Pollastri
We recently reported the medicinal chemistry re-optimization of a known human tyrosine kinase inhibitor, lapatinib, against a variety of parasites responsible for numerous tropical diseases, including: human African trypanosomiasis (Trypanosoma brucei), Chagas disease (T. cruzi), Leishmaniasis (Leishmania spp.) and malaria (Plasmodium falciparum). Herein, we report our continuing efforts to optimize this series against P. falciparum. Through the design of a library of compounds focused on reducing the lipophilicity and molecular weight, followed by an SAR exploration, we have identified NEU-1953 (40)...
January 4, 2018: ACS Infectious Diseases
Noelia Lander, Miguel A Chiurillo, Mayara S Bertolini, Roberto Docampo, Aníbal E Vercesi
The presence of a conserved mechanism for mitochondrial calcium uptake in trypanosomatids was crucial for the molecular identification of the mitochondrial calcium uniporter (MCU), a long-sought channel present in most eukaryotic organisms. Since then, research efforts to elucidate the role of MCU and its regulatory elements in different biological models have multiplied. MCU is the pore-forming subunit of a multimeric complex (the MCU complex or MCUC) and its predicted structure in trypanosomes is simpler than in mammalian cells, lacking two of its subunits and probably possessing other unidentified components...
December 29, 2017: Cell Biology International
Jeiczon Jaimes-Dueñez, Omar Triana-Chávez, Ana M Mejía-Jaramillo
Animal Trypanosomiasis (AT) is one of the most important problems in the Colombian livestock industry reducing its production around 30%. Caribbean and Orinoquia regions play a significant role in the development of this industry, having about 6.9 million cattle and 113,000 buffaloes. Considering the paucity in studies to understand the epidemiological features and control of AT in Colombia, the present study reports the seasonal transmission patterns and phylogeographic traits of the causal agents of AT in cattle and buffaloes from these regions...
January 15, 2018: Veterinary Parasitology
Michael P Pollastri
Decades after the last new chemical entity was added to the pharmacopeia for human African trypanosomiasis (or sleeping sickness), orally dosed fexinidazole stands poised to replace the current treatment regimen for Trypanosoma brucei gambiense infections, following a positive Phase 2/3 clinical trial.
December 20, 2017: Trends in Parasitology
Muna F Abry, Kelvin M Kimenyi, Daniel Masiga, Benard W Kulohoma
Accessory gland proteins (ACPs) are important reproductive proteins produced by the male accessory glands (MAGs) of most insect species. These proteins are essential for male insect fertility, and are transferred alongside semen to females during copulation. ACPs are poorly characterized in Glossina species (tsetse fly), the principal vector of the parasite that causes life-threatening Human African Trypanosomiasis and Animal trypanosomiasis in endemic regions in Africa. The tsetse fly has a peculiar reproductive cycle because of the absence of oviposition...
2017: Wellcome Open Research
Hela Abid, Emna Harigua-Souiai, Thouraya Mejri, Mourad Barhoumi, Ikram Guizani
BACKGROUND: The 5'-methylthioadenosine phosphorylase (MTAP), an enzyme involved in purine and polyamine metabolism and in the methionine salvage pathway, is considered as a potential drug target against cancer and trypanosomiasis. In fact, Trypanosoma and Leishmania parasites lack de novo purine pathways and rely on purine salvage pathways to meet their requirements. Herein, we propose the first comprehensive bioinformatic and structural characterization of the putative Leishmania infantum MTAP (LiMTAP), using a comparative computational approach...
December 19, 2017: BMC Structural Biology
Marleen Boelaert, Deby Mukendi, Emmanuel Bottieau, Jean Roger Kalo Lilo, Kristien Verdonck, Luigi Minikulu, Barbara Barbé, Philippe Gillet, Cédric P Yansouni, François Chappuis, Pascal Lutumba
OBJECTIVES: To estimate the diagnostic accuracy of HAT Sero K-SeT for the field diagnosis of second-stage human African trypanosomiasis (HAT). DESIGN: A phase III diagnostic accuracy design. Consecutive patients with symptoms clinically suggestive of HAT were prospectively enrolled. We compared results of the index test HAT Sero K-SeT with those of a composite reference standard: demonstration of trypanosomes in cerebrospinal fluid (CSF), or trypanosomes detected in any other body fluid AND white blood cell count in CSF >5/μl...
December 6, 2017: EBioMedicine
A S G Nefertiti, M M Batista, P B Da Silva, D G J Batista, C F Da Silva, R B Peres, E C Torres-Santos, E F Cunha-Junior, E Holt, D W Boykin, R Brun, T Wenzler, M N C Soeiro
The therapy for Human African Trypanosomiasis and Chagas Disease, caused by Trypanosoma brucei and Trypanosoma cruzi respectively, are limited providing minimal therapeutic options for the millions of individuals living in very poor communities. The effect of ten novel quinolines are evaluated herein through in silico and by phenotypic studies using in vitro and in vivo models. ADMET properties revealed that most molecules did not infringe Lipinski's rules, which is a prediction of good oral absorption. They showed good probability of CaCo2 permeability and for human intestinal absorption, low probability of mutagenicity and of hERG1 inhibition...
December 4, 2017: Antimicrobial Agents and Chemotherapy
Muthusamy Venkatraj, Irene G Salado, Jan Heeres, Jurgen Joossens, Paul J Lewi, Guy Caljon, Louis Maes, Pieter Van der Veken, Koen Augustyns
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...
November 27, 2017: European Journal of Medicinal Chemistry
Andrew M Thompson, Andrew J Marshall, Louis Maes, Nigel Yarlett, Cyrus J Bacchi, Eric Gaukel, Stephen A Wring, Delphine Launay, Stephanie Braillard, Eric Chatelain, Charles E Mowbray, William A Denny
A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead...
October 27, 2017: Bioorganic & Medicinal Chemistry Letters
(no author information available yet)
Human African Trypanosomiasis (HAT), a disease that provokes 2184 new cases a year in Sub-Saharan Africa, is caused by Trypanosoma brucei. Current treatments are limited, highly toxic, and parasite strains resistant to them are emerging. Therefore, there is an urgency to find new drugs against HAT. In this context, T. brucei depends on glycolysis as the unique source for ATP supply; therefore, the enzyme triosephosphate isomerase (TIM) is an attractive target for drug design. In the present work, three new benzimidazole derivatives were found as TbTIM inactivators (compounds 1, 2 and 3) with an I50 value of 84, 82 and 73 µM, respectively...
November 24, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Santiago Chávez, Guillermo Eastman, Pablo Smircich, Lorena Lourdes Becco, Carolina Oliveira-Rizzo, Rafael Fort, Mariana Potenza, Beatriz Garat, José Roberto Sotelo-Silveira, María Ana Duhagon
Trypanosoma cruzi is the protozoan parasite causing American trypanosomiasis or Chagas disease, a neglected parasitosis with important human health impact in Latin America. The efficacy of current therapy is limited, and its toxicity is high. Since parasite proliferation is a fundamental target for rational drug design, we sought to progress into its understanding by applying a genome-wide approach. Treating a TcI linage strain with hydroxyurea, we isolated epimastigotes in late G1, S and G2/M cell cycle stages at 70% purity...
2017: PloS One
Dennis Muhanguzi, Albert Mugenyi, Godfrey Bigirwa, Maureen Kamusiime, Ann Kitibwa, Grace Gloria Akurut, Sylvester Ochwo, Wilson Amanyire, Samuel George Okech, Jan Hattendorf, Robert Tweyongyere
BACKGROUND: Nagana (African Animal Trypanosomiasis-AAT) and tick-borne diseases (TBDs) constrain livestock production in most parts of sub-Saharan Africa. To this realisation, Uganda government set up an African trypanosomiasis (AT) control unit, which among other activities generates national tsetse control priority maps using apparent tsetse density data. Such maps underestimate mechanically transmitted AAT and thus ought to be refined using actual AT prevalence data. We therefore set out to generate up-to-date cattle and donkey trypanosomiasis prevalence data as well as find out the constraints to livestock production in Karamoja region in a bid to re-define AT control priority in this region...
November 25, 2017: BMC Veterinary Research
Ian Scoones, V Dzingirai, N Anderson, E MacLeod, L Mangwanya, F Matawa, A Murwira, L Nyakupinda, W Shereni, S C Welburn
Understanding the socio-ecology of disease requires careful attention to the role of patches within disease landscapes. Such patches, and the interfaces between different socio-epidemiological systems, we argue, have important implications for disease control. We conducted an interdisciplinary study over three years to investigate the spatial dynamics of human and animal trypanosomiasis in the Zambezi valley, Zimbabwe. We used a habitat niche model to identify changes in suitable habitat for tsetse fly vectors over time, and this is related to local villagers' understandings of where flies are found...
2017: Human Ecology: An Interdisciplinary Journal
Tsutomu Akama, Yong-Kang Zhang, Yvonne R Freund, Pamela Berry, Joanne Lee, Eric E Easom, Robert T Jacobs, Jacob J Plattner, Michael J Witty, Rosemary Peter, Tim G Rowan, Kirsten Gillingwater, Reto Brun, Bakela Nare, Luke Mercer, Musheng Xu, Jiangong Wang, Hao Liang
Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 values of 0.15 nM against T. congolense and 1.3 nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10 mg/kg against both T...
November 20, 2017: Bioorganic & Medicinal Chemistry Letters
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