scholarly journals Pharmacological Validation of Trypanosoma brucei Phosphodiesterases B1 and B2 as Druggable Targets for African Sleeping Sickness

2011 ◽  
Vol 54 (23) ◽  
pp. 8188-8194 ◽  
Author(s):  
Nicholas D. Bland ◽  
Cuihua Wang ◽  
Craig Tallman ◽  
Alden E. Gustafson ◽  
Zhouxi Wang ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Sleeping Sickness ◽  
African Sleeping Sickness ◽  
Druggable Targets

scholarly journals The Molecular Dynamics of Trypanosoma brucei UDP‐Galactose 4′‐Epimerase: A Drug Target for African Sleeping Sickness

2012 ◽  
Vol 80 (2) ◽  
pp. 173-181 ◽  
Author(s):  
Aaron J. Friedman ◽  
Jacob D. Durrant ◽  
Levi C. T. Pierce ◽  
Thomas J. McCorvie ◽  
David J. Timson ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Trypanosoma Brucei ◽  
Drug Target ◽  
Sleeping Sickness ◽  
African Sleeping Sickness

scholarly journals A global sensitivity analysis for African sleeping sickness

Parasitology ◽  
2010 ◽  
Vol 138 (4) ◽  
pp. 516-526 ◽  
Author(s):  
STEPHEN DAVIS ◽  
SERAP AKSOY ◽  
ALISON GALVANI
Keyword(s):  
Trypanosoma Brucei ◽  
Control Strategies ◽  
Sleeping Sickness ◽  
Sensitivity Analyses ◽  
Tsetse Flies ◽  
East African ◽  
African Sleeping Sickness ◽  
Regular Treatment ◽  
Global Sensitivity ◽  
Parameter Ranges

SUMMARYAfrican sleeping sickness is a parasitic disease transmitted through the bites of tsetse flies of the genus Glossina. We constructed mechanistic models for the basic reproduction number, R0, of Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, respectively the causative agents of West and East African human sleeping sickness. We present global sensitivity analyses of these models that rank the importance of the biological parameters that may explain variation in R0, using parameter ranges based on literature, field data and expertize out of Uganda. For West African sleeping sickness, our results indicate that the proportion of bloodmeals taken from humans by Glossina fuscipes fuscipes is the most important factor, suggesting that differences in the exposure of humans to tsetse are fundamental to the distribution of T. b. gambiense. The second ranked parameter for T. b. gambiense and the highest ranked for T. b. rhodesiense was the proportion of Glossina refractory to infection. This finding underlines the possible implications of recent work showing that nutritionally stressed tsetse are more susceptible to trypanosome infection, and provides broad support for control strategies in development that are aimed at increasing refractoriness in tsetse flies. We note though that for T. b. rhodesiense the population parameters for tsetse – species composition, survival and abundance – were ranked almost as highly as the proportion refractory, and that the model assumed regular treatment of livestock with trypanocides as an established practice in the areas of Uganda experiencing East African sleeping sickness.

scholarly journals A targeted delivery strategy for the development of potent trypanocides

2017 ◽  
Vol 53 (62) ◽  
pp. 8735-8738 ◽  
Author(s):  
Heeren M. Gordhan ◽  
Jillian E. Milanes ◽  
Yijian Qiu ◽  
Jennifer E. Golden ◽  
Kenneth A. Christensen ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Trypanosoma Brucei ◽  
Causative Agent ◽  
Targeted Delivery ◽  
Sleeping Sickness ◽  
African Sleeping Sickness ◽  
Delivery Strategy ◽  
New Drug

A new drug delivery strategy was investigated for the development of potent anti-parasitic compounds againstTrypanosoma brucei, the causative agent of African sleeping sickness.

scholarly journals RNA Interference-Mediated Silencing of Ornithine Decarboxylase and Spermidine Synthase Genes in Trypanosoma brucei Provides Insight into Regulation of Polyamine Biosynthesis

2009 ◽  
Vol 8 (5) ◽  
pp. 747-755 ◽  
Author(s):  
Yanjing Xiao ◽  
Diane E. McCloskey ◽  
Margaret A. Phillips
Keyword(s):  
Cell Death ◽  
Rna Interference ◽  
Trypanosoma Brucei ◽  
Ornithine Decarboxylase ◽  
Cellular Response ◽  
Sleeping Sickness ◽  
Spermidine Synthase ◽  
African Sleeping Sickness ◽  
Polyamine Biosynthesis ◽  
Insight Into

ABSTRACT Polyamine biosynthesis is a drug target for the treatment of African sleeping sickness; however, mechanisms regulating the pathway in Trypanosoma brucei are not well understood. Recently, we showed that RNA interference (RNAi)-mediated gene silencing or the inhibition of S-adenosylmethionine decarboxylase (AdoMetDC) led to the upregulation of the AdoMetDC activator, prozyme, and ornithine decarboxylase (ODC) proteins. To determine if this regulatory response is specific to AdoMetDC, we studied the effects of the RNAi-induced silencing of the spermidine synthase (SpdSyn) and ODC genes in bloodstream form T. brucei. The knockdown of either gene product led to the depletion of the polyamine and trypanothione pools and to cell death. Decarboxylated AdoMet levels were elevated, while AdoMet was not affected. There was no significant effect on the protein levels of other polyamine pathway enzymes. The treatment of parasites with the ODC inhibitor α-difluoromethylornithine gave similar results to those observed for ODC knockdown. Thus, the cellular response to the loss of AdoMetDC activity is distinctive, suggesting that AdoMetDC activity controls the expression levels of the other spermidine biosynthetic enzymes. RNAi-mediated cell death occurred more rapidly for ODC than for SpdSyn. Further, the ODC RNAi cells were rescued by putrescine, but not spermidine, suggesting that the depletion of both putrescine and spermidine is more detrimental than the depletion of spermidine alone. This finding may contribute to the effectiveness of ODC as a target for the treatment of African sleeping sickness, thus providing important insight into the mechanism of action of a key antitrypanosomal agent.

scholarly journals Trypanosoma brucei CTP synthetase: A target for the treatment of African sleeping sickness

2001 ◽  
Vol 98 (11) ◽  
pp. 6412-6416 ◽  
Author(s):  
A. Hofer ◽  
D. Steverding ◽  
A. Chabes ◽  
R. Brun ◽  
L. Thelander
Keyword(s):  
Trypanosoma Brucei ◽  
Sleeping Sickness ◽  
Ctp Synthetase ◽  
African Sleeping Sickness

scholarly journals Antitrypanosomal Activities of Tryptanthrins

2002 ◽  
Vol 46 (3) ◽  
pp. 882-883 ◽  
Author(s):  
John Scovill ◽  
Elizabeth Blank ◽  
Michael Konnick ◽  
Elizabeth Nenortas ◽  
Theresa Shapiro
Keyword(s):  
Trypanosoma Brucei ◽  
Antifungal Agent ◽  
Molecular Targets ◽  
Ring System ◽  
Effective Concentration ◽  
Sleeping Sickness ◽  
New Drugs ◽  
African Sleeping Sickness

ABSTRACT New drugs and molecular targets are needed against Trypanosoma brucei, the protozoan that causes African sleeping sickness. Tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione), a traditional antifungal agent, and 11 analogs were tested against T. brucei in vitro. The greatest activity was conferred by electron-withdrawing groups in the 8 position of the tryptanthrin ring system; the most potent compound had a 50% effective concentration of 0.40 μM.

scholarly journals Inhibitors Incorporating Zinc‐Binding Groups Target the GlcNAc‐PI de‐ N ‐acetylase in Trypanosoma brucei , the Causative Agent of African Sleeping Sickness

2012 ◽  
Vol 79 (3) ◽  
pp. 270-278 ◽  
Author(s):  
Nuha Z. Abdelwahab ◽  
Arthur T. Crossman ◽  
Lauren Sullivan ◽  
Michael A. J. Ferguson ◽  
Michael D. Urbaniak
Keyword(s):  
Trypanosoma Brucei ◽  
Causative Agent ◽  
Sleeping Sickness ◽  
Zinc Binding ◽  
African Sleeping Sickness
Sign in / Sign up

Export Citation Format

Share Document