scholarly journals Differential Inhibition of Human and Trypanosome Ubiquitin E1S by TAK-243 Offers Possibilities for Parasite Selective Inhibitors

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
D. Roeland Boer ◽  
Marie-José Bijlmakers
Keyword(s):  
Amino Acids ◽  
Trypanosoma Cruzi ◽  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Potent Inhibitor ◽  
Model System ◽  
Differential Inhibition ◽  
Protein Ubiquitination ◽  
Related Compounds

Abstract Novel strategies to target Trypanosoma brucei, Trypanosoma cruzi and Leishmania are urgently needed to generate better and safer drugs against Human African Trypanosomiasis, Chagas disease and Leishmaniasis, respectively. Here, we investigated the feasibility of selectively targeting in trypanosomatids the ubiquitin E1 activating enzyme (UBA1), an essential eukaryotic protein required for protein ubiquitination. Trypanosomatids contain two UBA1 genes in contrast to mammals and yeast that only have one, and using T. brucei as a model system, we show that both are active in vitro. Surprisingly, neither protein is inhibited by TAK-243, a potent inhibitor of human UBA1. This resistance stems from differences with the human protein at key amino acids, which includes a residue termed the gatekeeper because its mutation in E1s leads to resistance to TAK-243 and related compounds. Importantly, our results predict that trypanosomatid selective UBA1 inhibition is feasible and suggest ways to design novel compounds to achieve this.

scholarly journals Autoimmunity to phosphatidylserine and anemia in African Trypanosome infections

2021 ◽  
Vol 15 (9) ◽  
pp. e0009814
Author(s):  
Juan Rivera-Correa ◽  
Joseph Verdi ◽  
Julian Sherman ◽  
Jeremy M. Sternberg ◽  
Jayne Raper ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
B Cells ◽  
Trypanosoma Cruzi ◽  
Trypanosoma Brucei ◽  
Mouse Models ◽  
Human African Trypanosomiasis ◽  
Annexin V ◽  
Trypanosome Infection ◽  
Erythrocyte Plasma Membrane

Anemia caused by trypanosome infection is poorly understood. Autoimmunity during Trypanosoma brucei infection was proposed to have a role during anemia, but the mechanisms involved during this pathology have not been elucidated. In mouse models and human patients infected with malaria parasites, atypical B-cells promote anemia through the secretion of autoimmune anti-phosphatidylserine (anti-PS) antibodies that bind to uninfected erythrocytes and facilitate their clearance. Using mouse models of two trypanosome infections, Trypanosoma brucei and Trypanosoma cruzi, we assessed levels of autoantibodies and anemia. Our results indicate that acute T. brucei infection, but not T. cruzi, leads to early increased levels of plasma autoantibodies against different auto antigens tested (PS, DNA and erythrocyte lysate) and expansion of atypical B cells (ABCs) that secrete these autoantibodies. In vitro studies confirmed that a lysate of T. brucei, but not T. cruzi, could directly promote the expansion of these ABCs. PS exposure on erythrocyte plasma membrane seems to be an important contributor to anemia by delaying erythrocyte recovery since treatment with an agent that prevents binding to it (Annexin V) ameliorated anemia in T. brucei-infected mice. Analysis of the plasma of patients with human African trypanosomiasis (HAT) revealed high levels of anti-PS antibodies that correlated with anemia. Altogether these results suggest a relation between autoimmunity against PS and anemia in both mice and patients infected with T. brucei.

scholarly journals Cross-Resistance to Nitro Drugs and Implications for Treatment of Human African Trypanosomiasis

2010 ◽  
Vol 54 (7) ◽  
pp. 2893-2900 ◽  
Author(s):  
Antoaneta Y. Sokolova ◽  
Susan Wyllie ◽  
Stephen Patterson ◽  
Sandra L. Oza ◽  
Kevin D. Read ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Parent Drug ◽  
Cross Resistance ◽  
Pharmacokinetic Studies ◽  
African Trypanosomiasis ◽  
Trypanosoma Brucei Brucei ◽  
Resistant Lines

ABSTRACT The success of nifurtimox-eflornithine combination therapy (NECT) for the treatment of human African trypanosomiasis (HAT) has renewed interest in the potential of nitro drugs as chemotherapeutics. In order to study the implications of the more widespread use of nitro drugs against these parasites, we examined the in vivo and in vitro resistance potentials of nifurtimox and fexinidazole and its metabolites. Following selection in vitro by exposure to increasing concentrations of nifurtimox, Trypanosoma brucei brucei nifurtimox-resistant clones designated NfxR1 and NfxR2 were generated. Both cell lines were found to be 8-fold less sensitive to nifurtimox than parental cells and demonstrated cross-resistance to a number of other nitro drugs, most notably the clinical trial candidate fexinidazole (∼27-fold more resistant than parental cells). Studies of mice confirmed that the generation of nifurtimox resistance in these parasites did not compromise virulence, and NfxR1 remained resistant to both nifurtimox and fexinidazole in vivo. In the case of fexinidazole, drug metabolism and pharmacokinetic studies indicate that the parent drug is rapidly metabolized to the sulfoxide and sulfone form of this compound. These metabolites retained trypanocidal activity but were less effective in nifurtimox-resistant lines. Significantly, trypanosomes selected for resistance to fexinidazole were 10-fold more resistant to nifurtimox than parental cells. This reciprocal cross-resistance has important implications for the therapeutic use of nifurtimox in a clinical setting and highlights a potential danger in the use of fexinidazole as a monotherapy.

Growth of Enterobacter aerogenes in a lathyrogen-containing medium

1970 ◽  
Vol 16 (5) ◽  
pp. 398-400
Author(s):  
Joseph J. Aleo ◽  
Rodney F. Smith ◽  
Richard P. Ellen
Keyword(s):  
Minimal Medium ◽  
In Vitro Model ◽  
Enterobacter Aerogenes ◽  
Model System ◽  
In Vitro Model System ◽  
Vitro Model ◽  
Related Compounds ◽  
Beta Aminopropionitrile Fumarate ◽  
Experimental Lathyrism

Enterobacter aerogenes was examined for its ability to utilize a known lathyrogen or chemically related compounds for use in developing an in vitro model system to study experimental lathyrism. Enterobacter aerogenes grew in a minimal medium containing the lathyrogen, beta-aminopropionitrile fumarate. Related compounds or combinations of related compounds which together contained all the constituents of the lathyrogen failed to support growth. The specificity of this compound in supporting growth of this polysaccharide-producing microorganism suggests that this microorganism may be useful in developing an in vitro model system to study polysaccharide metabolism in experimental lathyrism.

scholarly journals Evaluating 5-Nitrothiazoles as Trypanocidal Agents

2015 ◽  
Vol 60 (2) ◽  
pp. 1137-1140 ◽  
Author(s):  
Ivan P. O'Shea ◽  
Mohammed Shahed ◽  
Benjamín Aguilera-Venegas ◽  
Shane R. Wilkinson
Keyword(s):  
Trypanosoma Brucei ◽  
Mammalian Cells ◽  
Cytotoxic Effect ◽  
Human African Trypanosomiasis ◽  
Type I ◽  
Antiparasitic Activity ◽  
Content Type ◽  
Growth Inhibitory ◽  
Activity Dependent ◽  
Related Compounds

ABSTRACTThe growth-inhibitory properties of a 5-nitrothiazole series were evaluated againstTrypanosoma brucei. A subset of related compounds displayed the greatest potency toward the parasite while exhibiting little cytotoxic effect on mammalian cells, with this antiparasitic activity dependent on expression of a type I nitroreductase by the trypanosome. We conclude that the 5-nitrothiazole class of nitroheterocyclic drugs may represent a new lead in the treatment of human African trypanosomiasis.

Utilization of amino acids by Trypanosoma brucei in culture: L-threonine as a precursor for acetate

Parasitology ◽  
1975 ◽  
Vol 71 (2) ◽  
pp. 311-326 ◽  
Author(s):  
G. A. M. Cross ◽  
R. A. Klein ◽  
D. J. Linstead
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Glutamic Acid ◽  
Trypanosoma Brucei ◽  
Potent Inhibitor ◽  
Culture Media ◽  
Growth Cycle ◽  
Defined Medium ◽  
Amino Acid Compositions

The amino acid compositions of several culture media have been analysed and compared. The utilization and excretion of amino acids and other metabolites have been followed during growth of Trypanosoma brucei S42 in a defined medium. All of the added L-threonine was metabolized by the cells, even when it was present at elevated concentrations. Glucose was consumed throughout the growth cycle: glutamine was consumed more rapidly than glutamic acid, which was itself used at about the same rate as proline. Threonine was cleaved to form glycine and acetate, both of which accumulated in the medium. Alanine and succinate were excreted together with a small amount of pyruvate, but these three products accounted for less than half of the glucose used. CO2 production from glucose was not measured, but insignificant amounts of CO2 were produced from threonine. Tetraethylthiuram disulphide blocked the cleavage of threonine and was a potent inhibitor of trypanosome growth.

scholarly journals In vitro and in vivo anti-Trypanosoma brucei activities of phenazinomycin and related compounds

2010 ◽  
Vol 63 (9) ◽  
pp. 579-581 ◽  
Author(s):  
Kazuhiko Otoguro ◽  
Aki Ishiyama ◽  
Masato Iwatsuki ◽  
Miyuki Namatame ◽  
Aki Nishihara-Tukashima ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Related Compounds

scholarly journals Synthesis of a Sugar-Based Thiosemicarbazone Series and Structure-Activity Relationship versus the Parasite Cysteine Proteases Rhodesain, Cruzain, and Schistosoma mansoni Cathepsin B1

2015 ◽  
Vol 59 (5) ◽  
pp. 2666-2677 ◽  
Author(s):  
Nayara Cristina Fonseca ◽  
Luana Faria da Cruz ◽  
Filipe da Silva Villela ◽  
Glaécia Aparecida do Nascimento Pereira ◽  
Jair Lage de Siqueira-Neto ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Schistosoma Mansoni ◽  
Trypanosoma Brucei ◽  
Chagas Disease ◽  
Cysteine Proteases ◽  
Content Type ◽  
Structure Activity ◽  
Biochemical Assays ◽  
The Impact

ABSTRACTThe pressing need for better drugs against Chagas disease, African sleeping sickness, and schistosomiasis motivates the search for inhibitors of cruzain, rhodesain, andSchistosoma mansoniCB1 (SmCB1), the major cysteine proteases fromTrypanosoma cruzi,Trypanosoma brucei, andS. mansoni, respectively. Thiosemicarbazones and heterocyclic analogues have been shown to be both antitrypanocidal and inhibitory against parasite cysteine proteases. A series of compounds was synthesized and evaluated against cruzain, rhodesain, and SmCB1 through biochemical assays to determine their potency and structure-activity relationships (SAR). This approach led to the discovery of 6 rhodesain, 4 cruzain, and 5 SmCB1 inhibitors with 50% inhibitory concentrations (IC50s) of ≤10 μM. Among the compounds tested, the thiosemicarbazone derivative of peracetylated galactoside (compound 4i) was discovered to be a potent rhodesain inhibitor (IC50= 1.2 ± 1.0 μM). The impact of a range of modifications was determined; removal of thiosemicarbazone or its replacement by semicarbazone resulted in virtually inactive compounds, and modifications in the sugar also diminished potency. Compounds were also evaluatedin vitroagainst the parasitesT. cruzi,T. brucei, andS. mansoni, revealing active compounds among this series.

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