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Sent on Wednesday, 2011 Oct 26Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Antimicrob Agents Chemother. 2011 Oct 24. [Epub ahead of print]Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues as Apoptotic Inducers with Activity against Experimental Visceral Leishmaniasis.Palit P, Hazra A, Maity A, Vijayan RS, Manoharan P, Banerjee S, Mondal NB, Ghoshal N, Ali N.SourceInfectious Diseases and Immunology Division, Indian Institute of Chemical Biology. AbstractNovel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Towards this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules as potential antileishmanials. 4-amino quinaldine derivatives presented inhibitory effects on L. donovani promatigotes and amastigotes (IC(50) ranging from 0.94 to 127 μM). Of these PP-9 and PP-10 were most effective in vitro and demonstrated strong efficacies in vivo through intraperitoneal route. They were also found to be effective against both sodium antimony gluconate sensitive and resistant Leishmania donovani strains in BALB/c mice when treated orally resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of DHFR and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments ROS generation, by evidenced from decreased GSH levels, and increased lipid peroxidation. Subsequent disruption of Leishmania promastigote mitochondrial membrane potential and activation of cytosolic proteases initiated the apoptotic pathway resulting in DNA fragmentation and parasite death. Our results demonstrate PP-9 and PP-10 as promising lead compounds with the potential for treating visceral leishmaniasis(VL) through oral route. |
| 2. | Chemotherapy. 2011 Oct 18;57(5):388-393. [Epub ahead of print]Protective Therapy with Novel Chromone Derivative against Leishmania donovani Inf ection Induces Th1 Response in vivo.Mallick S, Dutta A, Ghosh J, Maiti S, Mandal AK, Banerjee R, Bandyopadhyay C, Pal C.SourceCellular Immunology and Experimental Therapeutics Laboratory, Department of Zoology, West Bengal State University, Barasat, India. AbstractBackground: Visceral leishmaniasis is a chronic protozoan disease caused by Leishmania donovani, an obligatory intracellular parasite that resides and multiplies within macrophages of the reticuloendothelial system. The aim of this study was to evaluate the efficacy of nine novel synthetic chromone derivatives as antileishmanial molecules in experimental murine visceral leishmaniasis. Methods: In vitro activity of the molecules (2, 5 and 10 μg/ml) was assessed against promastigotes of both pentavalent antimonial-responsive strain AG83 and pentavalent antimonial-resistant strain GE1F8R at days 2 (48 h), 4 (96 h) and 6 (144 h). The efficacy of the most efficient chromone derivative [C-(6-Methyl-4-oxo-4H-1-benzopyran-3-yl)-N-(p-tolyl) nitrone], designated here as NP1, was also tested against intracellular amastigotes in vitro and in vivo. Results: NP1, 5 μg/ml, inhibited the growth of AG83 and GE1F8R promastigotes by 98.57% (day 4) and 75.75% (day 6), respectively, and also inhibited the growth of intracellular amastigotes by 85% (day 3), compared to DMSO control. Treatment of L. donovani-infected mice with NP1 resulted in a 70% significant decrease in parasite load in the spleen in the 7th week after infection (5 mice in each group), with associated induction of interferon-γ synthesis by dose 2 (37.5 mg/kg body weight) compared to DMSO control. Dose 2 was found efficient over dose 1 (25 mg/kg body weight). Conclusions: The novel synthetic chromone derivative is effective in the treatment of visceral leishmaniasis and induces the synthesis of interferon-γ in rodent models. Copyright © 2011 S. Karger AG, Basel. |
| 3. | Mol Biochem Parasitol. 2011 Oct 15. [Epub ahead of print]TbENF is an essential TbTFIIB-interacting trypanosomatid-specific factor.Solnoki KW, Sing AH, Sofa CJ, Miller R, Ogorzalek PA, Penek HV, Palenchar JB.SourceDepartment of Chemistry, Villanova University, 800 E. Lancaster Ave., Villanova, PA 19085, United States. AbstractTrypanosoma brucei, the causative agent of African Sleeping Sickness, is replete with unique biochemistry, including unusual features of gene transcription. The parasite also contains over 4500 non-annotated genes, representing novel biochemistry yet to be explored. Using tandem affinity purification (TAP)-tagged TbTFIIB, we identified and subsequently confirmed, one of the non-annotated T. brucei proteins, Tb11.02.4300, as a TbTFIIB-interacting protein. The 49kDa protein is nuclear and essential for parasite variability as determined by RNA interference studies; hence, the nomenclature T. brucei Essential Nuclear Factor (TbENF). TbENF is shown to interact with DNA in a sequence-independent fashion under the conditions examined. Furthermore, TbENF bears motifs associated with many eukaryotic transcription factors, such as a glutamine-rich region and a leucine zipper, yet TbENF is specific to trypanosomatids making it a potentially attractive therapeutic target. Taken together, our results suggest a role for TbENF in trypanosome gene transcription. Copyright © 2011. Published by Elsevier B.V. |
| 4. | J Med Chem. 2011 Oct 24. [Epub ahead of print]Novel 3-Nitro-1H-1,2,4-triazole-based Aliphatic and Aromatic Amines as anti-Chagasic Agents.Papadopoulou MV, Bourdin B, Bloomer WD, McKenzie C, Wilkinson SR, Prasittichai C, Brun R, Kaiser M, Torreele E.AbstractA series of novel 2-nitro-1H-imidazole- and 3-nitro-1H-1,2,4-triazole-based aromatic and aliphatic amines were screened for anti-trypanosomal activity and mammalian cytotoxicity by the Drugs for Neglected Diseases initiative (DNDi). Out of 42 compounds tested, eighteen 3-nitro-1,2,4-triazoles and one 2-nitroimidazole displayed significant growth inhibitory properties against T. cruzi amastigotes (IC<sub>50</sub> ranging from 40 nM to 1.97 µM) , without concomitant toxicity towards the host cells (L6 cells), having selectivity indices (SI) 44 to 1320. Most (16) of these active compounds were up to 33.8-fold more potent than the reference drug benznidazole, tested in parallel. Five novel 3-nitro-1,2,4-triazoles were active against bloodstream form (BSF) T. b. rhodesiense trypomastigotes (IC<sub>50</sub> at nM levels and SI 220 to 993). An NADH-dependent nitroreductase (TbNTR) plays a role in the anti-parasitic activity, since BSF T. b. brucei trypomastigotes with elevated TbNTR levels were hypersensitive to tested compounds. Therefore, a novel class of affordable 3-nitro-1,2,4-triazole-based compounds with antitrypanosomal activity has been identified. |
| 5. | J Med Chem. 2011 Oct 24. [Epub ahead of print]Pharmacological Validation of Trypanosoma brucei Phosphodiesterases B1 and B2 as Druggable Targets for African Sleeping Sickness.Bland ND, Wang C, Tallman C, Gustafson AE, Wang Z, Ashton TD, Ochiana SO, McAllister G, Cotter K, Fang AP, Gechijian L, Garceau N, Gangurde R, Ortenberg R, Ondrechen MJ, Campbell RK, Pollastri MP.AbstractNeglected tropical disease drug discovery requires application of pragmatic and efficient methods for development of new therapeutic agents. In this report we describe our target repurposing efforts for the essential phosphodiesterase (PDE) enzymes TbrPDEB1 and TbrPDEB2 of Trypanosoma brucei, the causative agent for human African trypanosomiasis (HAT). We describe protein expression and purification, assay development, and benchmark screening of a collection of 20 established human PDE inhibitors. We disclose that the human PDE4 inhibitor piclamilast, and some of its analogs, show modest inhibition of TbrPDEB1 and B2, and quickly kill the bloodstream form of the subspecies T. brucei brucei. We also report the development of a homology model of TbrPDEB1 that is useful for understanding the compound-enzyme interactions and for comparing the parasitic and human enzymes. Our profiling and early medicinal chemistry results strongly suggest that human PDE4 chemotypes represent a better starting point for optimization of TbrPDEB inhibitors than those that target any other human PDEs. |
| 6. | Essays Biochem. 2011 Oct 24;51:81-95.Intracellular growth and pathogenesis of Leishmania parasites.Naderer T, McConville MJ.SourceDepartment of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Flemington Rd, Parkville, VIC 3010, Australia. AbstractParasitic protozoa belonging to the genus Leishmania are the cause of a spectrum of diseases in humans, as well as chronic long-term infections. These parasites exhibit a remarkable capacity to survive and proliferate within the phagolysosome compartment of host macrophages. Studies with defined Leishmania mutants in mouse models of infection have highlighted processes that are required for parasite survival in macrophages. Parasite mutants have been identified that (i) are poorly virulent when the insect (promastigote) stage is used to initiate infection, but retain wild-type virulence following transformation to the obligate intracellular amastigote stage, (ii) are highly attenuated when either promastigotes or amastigotes are used, and (iii) are unable to induce characteristic lesion granulomas, but can persist within macrophages in other tissues. From these analyses it can be concluded that promastigote stages of some species require the surface expression of lipophosphoglycan, but not other surface components. Survival and subsequent proliferation of Leishmania in macrophages requires the activation of heat-shock responses (involving the up-regulation and/or phosphorylation of heat-shock proteins), the presence of oxidative and nitrosative defence mechanisms, and uptake and catabolism of carbon sources (glycoproteins, hexoses and amino acids) and essential nutrients (purines, amino acids and vitamins). Parasite mutants with defects in specific kinase/phosphatase-dependent signalling pathways are also severely attenuated in amastigote virulence, highlighting the potential importance of post-translational regulatory mechanisms in parasite adaptation to this host niche. |
| 7. | Essays Biochem. 2011 Oct 24;51:63-80.Folate metabolic pathways in Leishmania.Vickers TJ, Beverley SM.SourceDepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, U.S.A. AbstractTrypanosomatid parasitic protozoans of the genus Leishmania are autotrophic for both folate and unconjugated pteridines. Leishmania salvage these metabolites from their mammalian hosts and insect vectors through multiple transporters. Within the parasite, folates are reduced by a bifunctional DHFR (dihydrofolate reductase)-TS (thymidylate synthase) and by a novel PTR1 (pteridine reductase 1), which reduces both folates and unconjugated pteridines. PTR1 can act as a metabolic bypass of DHFR inhibition, reducing the effectiveness of existing antifolate drugs. Leishmania possess a reduced set of folate-dependent metabolic reactions and can salvage many of the key products of folate metabolism from their hosts. For example, they lack purine synthesis, which normally requires 10-formyltetrahydrofolate, and instead rely on a network of purine salvage enzymes. Leishmania elaborate at least three pathways for the synthesis of the key metabolite 5,10-methylene-tetrahydrofolate, required for the synthesis of thymidylate, and for 10-formyltetrahydrofolate, whose presumptive function is for methionyl-tRNAMet formylation required for mitochondrial protein synthesis. Genetic studies have shown that the synthesis of methionine using 5-methyltetrahydrofolate is dispensable, as is the activity of the glycine cleavage complex, probably due to redundancy with serine hydroxymethyltransferase. Although not always essential, the loss of several folate metabolic enzymes results in attenuation or loss of virulence in animal models, and a null DHFR-TS mutant has been used to induce protective immunity. The folate metabolic pathway provides numerous opportunities for targeted chemotherapy, with strong potential for 'repurposing' of compounds developed originally for treatment of human cancers or other infectious agents. |
| 8. | Essays Biochem. 2011 Oct 24;51:47-62.African trypanosomes: the genome and adaptations for immune evasion.Rudenko G.SourceDivision of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College London, Imperial College Road, South Kensington, London SW7 2AZ, U.K. AbstractThe African trypanosome Trypanosoma brucei is a flagellated unicellular parasite transmitted by tsetse flies that causes African sleeping sickness in sub-Saharan Africa. Trypanosomes are highly adapted for life in the hostile environment of the mammalian bloodstream, and have various adaptations to their cell biology that facilitate immune evasion. These include a specialized morphology, with most nutrient uptake occurring in the privileged location of the flagellar pocket. In addition, trypanosomes show extremely high rates of recycling of a protective VSG (variant surface glycoprotein) coat, whereby host antibodies are stripped off of the VSG before it is re-used. VSG recycling therefore functions as a mechanism for cleaning the VSG coat, allowing trypanosomes to survive in low titres of anti-VSG antibodies. Lastly, T. brucei has developed an extremely sophisticated strategy of antigenic variation of its VSG coat allowing it to evade host antibodies. A single trypanosome has more than 1500 VSG genes, most of which are located in extensive silent arrays. Strikingly, most of these silent VSGs are pseudogenes, and we are still in the process of trying to understand how non-intact VSGs are recombined to produce genes encoding functional coats. Only one VSG is expressed at a time from one of approximately 15 telomeric VSG ES (expression site) transcription units. It is becoming increasingly clear that chromatin remodelling must play a critical role in ES control. Hopefully, a better understanding of these unique trypanosome adaptations will eventually allow us to disrupt their ability to multiply in the mammalian bloodstream. |
| 9. | Essays Biochem. 2011 Oct 24;51:31-46.Gene expression regulation in trypanosomatids.De Gaudenzi JG, Noé G, Campo VA, Frasch AC, Cassola A.SourceInstituto de Investigaciones Biotecnológicas - Instituto Tecnológico Chascomús, UNSAM-CONICET, Av. Gral. Paz 5445, INTI, Edificio 24, 1650 San Martín, Provincia de Buenos Aires, Argentina. AbstractTrypanosomatids are protozoan micro-organisms that cause serious health problems in humans and domestic animals. In addition to their medical relevance, these pathogens have novel biological structures and processes. From nuclear DNA transcription to mRNA translation, trypanosomes use unusual mechanisms to control gene expression. For example, transcription by RNAPII (RNA polymerase II) is polycistronic, and only a few transcription initiation sites have been identified so far. The sequences present in the polycistronic units code for proteins having unrelated functions, that is, not involved in a similar metabolic pathway. Owing to these biological constraints, these micro-organisms regulate gene expression mostly by post-transcriptional events. Consequently, the function of proteins that recognize RNA elements preferentially at the 3' UTR (untranslated region) of transcripts is central. It was recently shown that mRNP (messenger ribonucleoprotein) complexes are organized within post-transcriptional operons to co-ordinately regulate gene expression of functionally linked transcripts. In the present chapter we will focus on particular characteristics of gene expression in the so-called TriTryp parasites: Trypanosoma cruzi, Trypanosoma brucei and Leishmania major. |
| 10. | Vector Borne Zoonotic Dis. 2011 Oct 24. [Epub ahead of print]Vector-Borne Diseases in Client-Owned and Stray Cats from Madrid, Spain.Ayllón T, Diniz PP, Breitschwerdt EB, Villaescusa A, Rodríguez-Franco F, Sainz A.Source1 Departamento de Medicina y Cirugía Animal, Facultad de Veterinaria, Universidad Complutense de Madrid , Madrid, Spain . AbstractAbstract The role of various vector-borne pathogens as a cause of disease in cats has not been clearly determined. The current study evaluated risk factors, clinical and laboratory abnormalities associated with Ehrlichia spp., Anaplasma spp., Neorickettsia spp., Leishmania spp., and Bartonella spp. infection or exposure in 680 client-owned and stray cats from Madrid, Spain. Our results indicate that a large portion (35.1%) of the cat population of Madrid, Spain, is exposed to at least one of the five vector-borne pathogens tested. We found seroreactivity to Bartonella henselae in 23.8%, to Ehrlichia canis in 9.9%, to Anaplasma phagocytophilum in 8.4%, to Leishmania infantum in 3.7%, and to Neorickettsia risticii in 1% of the feline study population. About 9.9% of cats had antibody reactivity to more than one agent. L. infantum DNA was amplified from four cats (0.6%), B. henselae DNA from one cat (0.15%), and B. clarridgeiae DNA from another cat (0.15%). |
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