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Sent on Friday, 2009 Nov 20Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | ChemMedChem. 2009 Nov 18. [Epub ahead of print]Investigation of Trypanothione Reductase as a Drug Target in Trypanosoma brucei.Spinks D, Shanks EJ, Cleghorn LA, McElroy S, Jones D, James D, Fairlamb AH, Frearson JA, Wyatt PG, Gilbert IH.Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH (UK), Fax: (+44) 1382-386-373. There is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human African trypanosomiasis, which is caused by Trypanosoma brucei. The enzyme trypanothione reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62 000 compound library against T. brucei TryR. Further work was undertaken to optimise potency and selectivity of two novel-compound series arising from the enzymatic and whole parasite screens and mammalian cell counterscreens. Both of these series, containing either a quinoline or pyrimidinopyrazine scaffold, yielded low micromolar inhibitors of the enzyme and growth of the parasite. The challenges of inhibiting TryR with druglike molecules is discussed. |
| PMID: 19924760 [PubMed - as supplied by publisher] | |
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| 2. | Acta Crystallogr Sect F Struct Biol Cryst Commun. 2009 Nov 1;65(Pt 11):1116-1119. Epub 2009 Oct 30.Production, purification, crystallization and preliminary X-ray diffraction studies of the nucleoside diphosphate kinase b from Leishmania major.Tonoli CC, Vieira PS, Ward RJ, Arni RK, de Oliveira AH, Murakami MT.Center for Structural Molecular Biology, Brazilian Association for Synchrotron Light Technology, Campinas-SP, Brazil. |
| PMID: 19923730 [PubMed - as supplied by publisher] | |
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| 3. | Acta Crystallogr D Biol Crystallogr. 2009 Nov 1;65(Pt 11):1187-1195. Epub 2009 Oct 22.Structure of cyclophilin from Leishmania donovani bound to cyclosporin at 2.6 A resolution: correlation between structure and thermodynamic data.Venugopal V, Datta AK, Bhattacharyya D, Dasgupta D, Banerjee R.Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Sector 1, Block AF, Bidhannagar, Kolkata 700 064, India. Drug development against Leishmania donovani, the pathogen that causes visceral leishmaniasis in humans, is currently an active area of research given the widespread prevalence of the disease and the emergence of resistant strains. The immunosuppressive drug cyclosporin is known to have antiparasitic activity against a variety of pathogens. The receptor for cyclosporin is the protein cyclophilin, which is a ubiquitous peptidylprolyl isomerase. The crystal structure of cyclophilin from L. donovani complexed with cyclosporin has been solved at 2.6 A resolution. The thermodynamic parameters of the interaction have been determined using spectroscopic and calorimetric techniques. A detailed effort has been made to predict the thermodynamic parameters of binding from computations based on the three-dimensional crystal structure. These results were in good agreement with the corresponding experimental values. Furthermore, the structural and biophysical results have been discussed in the context of leishmanial drug resistance and could also set the stage for the design of potent non-immunosuppressive antileishmanials. |
| PMID: 19923714 [PubMed - as supplied by publisher] | |
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| 4. | J Clin Microbiol. 2009 Nov 18. [Epub ahead of print]Asymptomatic Leishmania infantum infection in a tra ditionally non-endemic area of North-western Italy (Piemonte region).Biglino A, Bolla C, Concialdi E, Trisciuoglio A, Romano A, Ferroglio E.Department of Clinical and Biological Sciences, University of Torino, Infectious Diseases Unit, Corso Dante 202, 10141 ASTI (Italy); Department of Animal Production, Epidemiology and Ecology, University of Torino, Via L. da Vinci 44, 10095 GRUGLIASCO, Italy. The prevalence of Leishmania infantum specific antibodies and asymptomatic infection was assessed in a randomised sample of 526 healthy adults from a non-endemic continental area of Northwestern Italy, where autochtonous cases of visceral leishmaniasis (VL) were recently reported. L. infantum- specific antibodies were detected by Western-blot (WB) in 39 subjects (7.41%), while L. infantum k-DNA was amplified from buffy-coat in 21 out of 39 WB-positive, confirming asymptomatic infection in 53.8% of seropositives. Risk factors significantly associated with WB positivity were: uninterrupted residence since childhood in local rural environment (Odds Ratio [O.R.] 3.5; 95% C.I. 1.7 - 7.3); daily contact with animals -though not exclusively with dogs- (O.R. 3.7; 95% C.I. 1.3 -10.7); older age (O.R. 2.31; 95% C.I. 1.2 - 4.5); and agriculture / other outdoor activities (O.R. 3.8; 95% C.I. 0.99 - 3.7. Logistic regression analysis showed that uninterrupted residence in local rural environment, and age > 65 years were the only independent predictors of seropositivity assessed by WB. Follow-up at 24 months did not show evidence of VL in either seropositive or PCR-positive subjects. The detection of a high seroprevalence rate -confirmed as asymptomatic infection by PCR in more than half of cases- among healthy residents in a continental area of North-Western Italy, makes local L. infantum transmission very likely. In a region where VL is considered as non-endemic, these findings warrant further epidemiological investigations as well as interventions on both canine reservoir and vectors, considering possible risks for immunosuppressed patients. |
| PMID: 19923480 [PubMed - as supplied by publisher] | |
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| 5. | J Immunol. 2009 Dec 1;183(11):6859.Comment on "TLR9-Dependent Activation of Dendritic Cells by DNA from Leishmania major Favors Th1 Cell Development and the Resolution of Lesions"Bogdan C, Schleicher U.Microbiology Institute, Clinical Microbiology, Immunology, and Hygiene, University Clinic of Erlangen. |
| PMID: 19923471 [PubMed - as supplied by publisher] | |
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| 6. | J Immunol. 2009 Nov 18. [Epub ahead of print]Neutrophils and Macrophages Cooperate in Host Resistance against Leishmania braziliensis Infection.Novais FO, Santiago RC, Báfica A, Khouri R, Afonso L, Borges VM, Brodskyn C, Barral-Netto M, Barral A, de Oliveira CI.*Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil; Neutrophils play an active role in the control of infections caused by intracellular pathogens such as Leishmania. In the present study, we investigated the effect of neutrophil depletion at the time of Leishmania braziliensis infection of BALB/c mice and how neutrophils interact with the infected macrophage to promote parasite elimination. The in vivo depletion of neutrophils led to a significant increase in parasite load and enhanced the Th1-Th2 immune response in this experimental model of infection. BALB/c mice coinoculated with both parasites and live neutrophils displayed lower parasite burdens at the site of infection and in the draining lymph nodes. In vitro, we observed that live neutrophils significantly reduced the parasite load in L. braziliensis-infected murine macrophages, an effect not observed with Leishmania major. L. braziliensis elimination was dependent on the interaction between neutrophils and macrophages and was associated with TNF-alpha as well as superoxide production. Furthermore, cooperation between neutrophils and macrophages toward parasite elimination was also observed in experiments performed with L. braziliensis-infected human cells and, importantly, with two other New World Leishmania species. These results indicate that neutrophils play an important and previously unappreciated role in L. braziliensis infection, favoring the induction of a protective immune response. |
| PMID: 19923470 [PubMed - as supplied by publisher] | |
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| 7. | J Immunol. 2009 Nov 18. [Epub ahead of print]Infection with Arginase-Deficient Leishmania major Reveals a Parasite Number-Dependent and Cytokine-Independent Regulation of Host Cellular Arginase Activity and Disease Pathogenesis.Muleme HM, Reguera RM, Berard A, Azinwi R, Jia P, Okwor IB, Beverley S, Uzonna JE.*Department of Immunology, University of Manitoba, Winnipeg, Manitoba Canada. The balance between the products of l-arginine metabolism in macrophages regulates the outcome of Leishmania major infection. l-arginine can be oxidized by host inducible NO synthase to produce NO, which contributes to parasite killing. In contrast, l-arginine hydrolysis by host arginase blocks NO generation and provides polyamines, which can support parasite proliferation. Additionally, Leishmania encode their own arginase which has considerable potential to modulate infectivity and disease pathogenesis. In this study, we compared the infectivity and impact on host cellular immune response in vitro and in vivo of wild-type (WT) L. major with that of a parasite arginase null mutant (arg(-)) L. major. We found that arg(-) L. major are impaired in their macrophage infectivity in vitro independent of host inducible NO synthase activities. As with in vitro results, the proliferation of arg(-) L. major in animal infections was also significantly impaired in vivo, resulting in delayed onset of lesion development, attenuated pathology, and low parasite burden. Despite this attenuated pathology, the production of cytokines by cells from the draining lymph node of mice infected with WT and arg(-) L. major was similar at all times tested. Interestingly, in vitro and in vivo arginase levels were significantly lower in arg(-) than in WT-infected cases and were directly correlated with parasite numbers inside infected cells. These results suggest that Leishmania-encoded arginase enhances disease pathogenesis by augmenting host cellular arginase activities and that contrary to previous in vitro studies, the host cytokine response does not influence host arginase activity. |
| PMID: 19923451 [PubMed - as supplied by publisher] | |
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| 8. | J Immunol. 2009 Nov 18. [Epub ahead of print]Enhanced Susceptibility to Leishmania Infection in Resistant Mice in the Absence of Immediate Early Response Gene X-1.Akilov OE, Ustyugova IV, Zhi L, Hasan T, Wu MX.Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, MA 02114. Immediate early response gene X-1 (IEX-1) is a stress-inducible gene abundantly expressed in macrophages and T cells following various stimuli. To explore a potential role for IEX-1 in control of the susceptibility to Leishmania major infection, the inflammatory response during cutaneous leishmaniasis was evaluated in 129Sv/C57BL/6-resistant mice in the presence or absence of IEX-1. Null mutation of IEX-1 enhanced the susceptibility of the mice to L. major infection, and aggravated inflammatory responses in comparison with wild-type control mice. The excessive inflammation was not ascribed to a Th2-biased immune response or a defect in Th1 polarization, but rather to an elevated level of IL-17 production by both gammadelta T and CD4(+) cells, concomitant with an increase of the neutrophil recruitment early in the infection. The lack of IEX-1 also suppressed TNF-alpha production in both macrophages and T cells, resulting in a high intralesional load of parasites and delayed healing of the lesion, both of which were reversed by TNF-alpha treatment. These findings indicate the crucial role of IL-17 and TNF-alpha in determining the outcome of L. major infection beyond a balance between Th1- and Th2-mediated immune responses. |
| PMID: 19923449 [PubMed - as supplied by publisher] | |
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| 9. | J Biol Chem. 2009 Nov 18. [Epub ahead of print]Identification of transpo rt-critical residues in a folate transporter from the folate-biopterin transporter (FBT) family.Eudes A, Kunji ER, Noiriel A, Klaus SM, Vickers TJ, Beverley SM, Gregory JF, Hanson AD.University of Florida, United States; The Synechocystis Slr0642 protein and its plastidial Arabidopsis (Arabidopsis thaliana) ortholog At2g32040 belong to the folate-biopterin transporter (FBT) family within the major facilitator superfamily. Both transport folates when expressed in Escherichia coli. As the structural requirements for transport activity are not known for any FBT protein, we applied mutational analysis to identify residues that are critical to transport and interpreted the results using a comparative structural model based on E. coli lactose permease. Folate transport was assessed via the growth of an E. coli pabA abgT strain, which cannot synthesize or take up folates or p -aminobenzoylglutamate. In total, 47 residues were replaced with Cys or Ala. Mutations at 22 positions abolished folate uptake without affecting Slr0642 expression in membranes, whereas other mutations had no effect. Residues important for function mostly line the predicted central cavity and are concentrated in the core alpha-helices H1, H4, H7, and H10. The essential residue locations are consistent with a folate-binding site lying roughly equidistant from both faces of the transporter. Arabidopsis has eight other FBT proteins besides At2g32040, often lacking conserved critical residues. When six of these proteins were expressed in E. coli or in Leishmania folate or pterin transporter mutants none showed evidence of folate or pterin transport activity, and only At2g32040 was isolated by functional screening of Arabidopsis cDNA libraries in E. coli. Such negative data could reflect roles in transport of other substrates. These studies provide first insights into the native structure and catalytic mechanism of FBT family carriers. |
| PMID: 19923217 [PubMed - as supplied by publisher] | |
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| 10. | J Biol Chem. 2009 Nov 18. [Epub ahead of print]Crystal structures of Trypanosoma brucei sterol 14 alpha-demethylase and implications for selective treatment of human infections.Lepesheva GI, Park HW, Hargrove TY, Vanhollebeke B, Wawrzak Z, Harp JM, Sundaramoorthy M, Nes WD, Pays E, Chaudhuri M, Villalta F, Waterman MR.Vanderbilt University, United States; Sterol 14 alpha-demethylase (14DM, the CYP51 family of cytochrome P450) is an essential enzyme in sterol biosynthesis in eukaryotes. It serves as a major drug target for fungal diseases and can potentially become a target for treatment of human infections with protozoa. Here we present 1.9 Angstrom resolution crystal structures of 14DM from the protozoan pathogen Trypanosoma brucei, ligand free and complexed with a strong chemically selected inhibitor N-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadi-azol-2-yl)benzamide that we previously found to produce potent antiparasitic effects in Trypanosomatidae. This is the first structure of a eukaryotic microsomal 14DM that acts on sterol biosynthesis, and it differs profoundly from that of the water soluble CYP51 family member from Mycobacterium tuberculosis, both in organization of the active site cavity and in the substrate access channel location. Inhibitor binding does not cause large-scale conformational rearrangements, yet induces unanticipated local alterations in the active site, including formation of a hydrogen bond network that connects, via the inhibitor amide group fragment, two remote functionally essential protein segments and alters the heme environment. The inhibitor binding mode provides a possible explanation for both its functionally irreversible effect on the enzyme activity and its selectivity towards the 14DM from human pathogens versus the human 14DM ortholog. The structures shed new light on 14DM functional conservation and open an excellent opportunity for directed design of novel antiparasitic drugs. |
| PMID: 19923211 [PubMed - as supplied by publisher] | |
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