scholarly journals Trypanocidal Activity of 8-Methyl-5′-{[(Z)-4-Aminobut-2-enyl]-(Methylamino)}Adenosine (Genz-644131), an Adenosylmethionine Decarboxylase Inhibitor

2009 ◽  
Vol 53 (8) ◽  
pp. 3269-3272 ◽  
Author(s):  
Cyrus J. Bacchi ◽  
Robert H. Barker ◽  
Aixa Rodriguez ◽  
Bradford Hirth ◽  
Donna Rattendi ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Dose Range ◽  
System Model ◽  
Drug Resistant ◽  
Trypanosoma Brucei Rhodesiense ◽  
Trypanosoma Brucei Brucei ◽  
African Trypanosomes ◽  
Adenosylmethionine Decarboxylase ◽  
Daily Dose ◽  
Purine Ring

ABSTRACT Genzyme 644131, 8-methyl-5′-{[(Z)-4-aminobut-2-enyl](methylamino)}adenosine, is an analog of the enzyme activated S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor and the trypanocidal agent MDL-7381, 5-{[(Z)-4-aminobut-2-enyl](methylamino)}adenosine. The analog differs from the parent in having an 8-methyl group on the purine ring that bestows favorable pharmacokinetic, biochemical, and trypanocidal activities. The compound was curative in acute Trypanosoma brucei brucei and drug-resistant Trypanosoma brucei rhodesiense model infections, with single-dose activity in the 1- to 5-mg/kg/day daily dose range for 4 days against T. brucei brucei and 25- to 50-mg/kg twice-daily dosing against T. brucei rhodesiense infections. The compound was not curative in the TREU 667 central nervous system model infection but cleared blood parasitemia and extended time to recrudescence in several groups. This study shows that AdoMetDC remains an attractive chemotherapeutic target in African trypanosomes and that chemical changes in AdoMetDC inhibitors can produce more favorable drug characteristics than the lead compound.

scholarly journals In Vitro Generation of Human High-Density-Lipoprotein-Resistant Trypanosoma brucei brucei

2006 ◽  
Vol 5 (8) ◽  
pp. 1276-1286 ◽  
Author(s):  
Sara D. Faulkner ◽  
Monika W. Oli ◽  
Rudo Kieft ◽  
Laura Cotlin ◽  
Justin Widener ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Trypanosoma Brucei ◽  
Density Lipoprotein ◽  
High Density ◽  
Surface Glycoprotein ◽  
Trypanosoma Brucei Brucei ◽  
African Trypanosomes ◽  
Expression Site ◽  
Human High Density Lipoprotein

ABSTRACT The host range of African trypanosomes is influenced by innate protective molecules in the blood of primates. A subfraction of human high-density lipoprotein (HDL) containing apolipoprotein A-I, apolipoprotein L-I, and haptoglobin-related protein is toxic to Trypanosoma brucei brucei but not the human sleeping sickness parasite Trypanosoma brucei rhodesiense. It is thought that T. b. rhodesiense evolved from a T. b. brucei-like ancestor and expresses a defense protein that ablates the antitrypanosomal activity of human HDL. To directly investigate this possibility, we developed an in vitro selection to generate human HDL-resistant T. b. brucei. Here we show that conversion of T. b. brucei from human HDL sensitive to resistant correlates with changes in the expression of the variant surface glycoprotein (VSG) and abolished uptake of the cytotoxic human HDLs. Complete transcriptome analysis of the HDL-susceptible and -resistant trypanosomes confirmed that VSG switching had occurred but failed to reveal the expression of other genes specifically associated with human HDL resistance, including the serum resistance-associated gene (SRA) of T. b. rhodesiense. In addition, we found that while the original active expression site was still utilized, expression of three expression site-associated genes (ESAG) was altered in the HDL-resistant trypanosomes. These findings demonstrate that resistance to human HDLs can be acquired by T. b. brucei.

Activity of Extracts and Naphthoquinones from Kigelia pinnata Against Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense

Planta Medica ◽  
1999 ◽  
Vol 65 (6) ◽  
pp. 536-540 ◽  
Author(s):  
S. V.K. Moideen ◽  
P. J. Houghton ◽  
P. Rock ◽  
S. L. Croft ◽  
F. Aboagye-Nyame
Keyword(s):  
Trypanosoma Brucei ◽  
Trypanosoma Brucei Rhodesiense ◽  
Trypanosoma Brucei Brucei ◽  
Kigelia Pinnata

scholarly journals Multiple Genetic Mechanisms Lead to Loss of Functional TbAT1 Expression in Drug-Resistant Trypanosomes

2009 ◽  
Vol 9 (2) ◽  
pp. 336-343 ◽  
Author(s):  
Mhairi L. Stewart ◽  
Richard J. S. Burchmore ◽  
Caroline Clucas ◽  
Christiane Hertz-Fowler ◽  
Karen Brooks ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Drug Resistant ◽  
Diminazene Aceturate ◽  
Content Type ◽  
African Trypanosomes ◽  
Genomic Location ◽  
Adenosine Uptake ◽  
Resistant Lines ◽  
The Status ◽  
Genetic Mechanisms

ABSTRACT The P2 aminopurine transporter, encoded by TbAT1 in African trypanosomes in the Trypanosoma brucei group, carries melaminophenyl arsenical and diamidine drugs into these parasites. Loss of this transporter contributes to drug resistance. We identified the genomic location of TbAT1 to be in the subtelomeric region of chromosome 5 and determined the status of the TbAT1 gene in two trypanosome lines selected for resistance to the melaminophenyl arsenical, melarsamine hydrochloride (Cymelarsan), and in a Trypanosoma equiperdum clone selected for resistance to the diamidine, diminazene aceturate. In the Trypanosoma brucei gambiense STIB 386 melarsamine hydrochloride-resistant line, TbAT1 is deleted, while in the Trypanosoma brucei brucei STIB 247 melarsamine hydrochloride-resistant and T. equiperdum diminazene-resistant lines, TbAT1 is present, but expression at the RNA level is no longer detectable. Further characterization of TbAT1 in T. equiperdum revealed that a loss of heterozygosity at the TbAT1 locus accompanied loss of expression and that P2-mediated uptake of [3H]diminazene is lost in drug-resistant T. equiperdum. Adenine-inhibitable adenosine uptake is still detectable in a ΔTbat1 T. b. brucei mutant, although at a greatly reduced capacity compared to that of the wild type, indicating that an additional adenine-inhibitable adenosine permease, distinct from P2, is present in these cells.

scholarly journals The Trypanocide Diminazene Aceturate Is Accumulated Predominantly through the TbAT1 Purine Transporter: Additional Insights on Diamidine Resistance in African Trypanosomes

2004 ◽  
Vol 48 (5) ◽  
pp. 1515-1519 ◽  
Author(s):  
Harry P. de Koning ◽  
Laura F. Anderson ◽  
Mhairi Stewart ◽  
Richard J. S. Burchmore ◽  
Lynsey J. M. Wallace ◽  
...  
Keyword(s):  
Cell Line ◽  
Trypanosoma Brucei ◽  
Domestic Animals ◽  
Trypanosoma Brucei Brucei ◽  
Diminazene Aceturate ◽  
Severe Problem ◽  
African Trypanosomes ◽  
Detectable Rate ◽  
Almost All ◽  
Null Mutants

ABSTRACT Resistance to diminazene aceturate (Berenil) is a severe problem in the control of African trypanosomiasis in domestic animals. It has been speculated that resistance may be the result of reduced diminazene uptake by the parasite. We describe here the mechanisms by which [3H]diminazene is transported by Trypanosoma brucei brucei bloodstream forms. Diminazene was rapidly accumulated through a single transporter, with a Km of 0.45 ± 0.11 μM, which was dose dependently inhibited by pentamidine and adenosine. The Ki values for these inhibitors were consistent with this transporter being the P2/TbAT1 adenosine transporter. Yeast expressing TbAT1 acquired the ability to take up [3H]diminazene and [3H]pentamidine. TbAT1-null mutants had lost almost all capacity for [3H]diminazene transport. However, this cell line still displayed a small but detectable rate of [3H]diminazene accumulation, in a nonsaturable manner. We conclude that TbAT1 mediates [3H]diminazene transport almost exclusively and that this explains the observed diminazene resistance phenotypes of TbAT1-null mutants and field isolates.

scholarly journals Differential virulence of Trypanosoma brucei rhodesiense isolates does not influence the outcome of treatment with anti-trypanosomal drugs in the mouse model

2020 ◽  
Author(s):  
Kariuki Ndung’u ◽  
Grace Adira Murilla ◽  
John Kibuthu Thuita ◽  
Geoffrey Njuguna Ngae ◽  
Joanna Eseri Auma ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Post Infection ◽  
Drug Resistant ◽  
Weight Changes ◽  
Trypanosoma Brucei Rhodesiense ◽  
Diminazene Aceturate ◽  
Reference Drug ◽  
Western Kenya ◽  
Biotechnology Research ◽  
Cure Rates

AbstractWe assessed the virulence and anti-trypanosomal drug sensitivity patterns of Trypanosoma brucei rhodesiense (Tbr) isolates in the Kenya Agricultural and Livestock Research Organization-Biotechnology Research Institute (KALRO-BioRI) cryobank. Specifically, the study focused on Tbr clones originally isolated from the western Kenya/eastern Uganda focus of human African Trypanosomiasis (HAT). Twelve (12) Tbr clones were assessed for virulence using groups(n=10) of Swiss White Mice monitored for 60 days post infection (dpi). Based on survival time, four classes of virulence were identified: (a) very-acute: 0-15, (b) acute: 16-30, (c) sub-acute: 31-45 and (d) chronic: 46-60 dpi. Other virulence biomarkers identified included: prepatent period (pp), parasitaemia progression, packed cell volume (PCV) and body weight changes. The test Tbr clones together with KALRO-BioRi reference drug-resistant and drug sensitive isolates were then tested for sensitivity to melarsoprol (mel B) pentamidine, diminazene aceturate and suramin, using mice groups (n= 5) treated with single doses of each drug at 24 hours post infection. Our results showed that the clones were distributed among four classes of virulence as follows: 3/12 (very-acute), 3/12 (acute), 2/12 (sub-acute) and 4/12 (chronic) isolates. Differences in survivorship, parasitaemia progression and PCV were significant (P<0.001) and correlated. The isolate considered to be drug resistant at KALRO-BioRI, KETRI 2538, was confirmed to be resistant to melarsoprol, pentamidine and diminazene aceturate but it was not resistant to suramin. At least 80% cure rates of all the test isolates was achieved with melarsoprol (1mg/Kg and 20 mg/kg), pentamidine (5 and 20 mg/kg), diminazene aceturate (5 mg/kg) and suramin (5 mg/kg) indicating that the isolates were not resistant to any of the drugs despite the differences in virulence. This study provides evidence of variations in virulence of Tbr isolates from a single HAT focus and confirms that these variations are not a significant determinant of isolate sensitivity to anti-trypanosomal drugs.

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