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Sent on Saturday, 2009 Mar 28Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
- 1: PLoS ONE. 2009;4(3):e4918. Epub 2009 Mar 26.
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HIV aspartyl peptidase inhibitors interfere with cellular proliferation, ultrastructure and macrophage infection of Leishmania amazonensis.
Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, RJ, Brazil.
BACKGROUND: Leishmania is the etiologic agent of leishmanisais, a protozoan disease whose pathogenic events are not well understood. Current therapy is suboptimal due to toxicity of the available therapeutic agents and the emergence of drug resistance. Compounding these problems is the increase in the number of cases of Leishmania-HIV coinfection, due to the overlap between the AIDS epidemic and leishmaniasis. METHODOLOGY/PRINCIPAL FINDINGS: In the present report, we have investigated the effect of HIV aspartyl peptidase inhibitors (PIs) on the Leishmania amazonensis proliferation, ultrastructure, interaction with macrophage cells and expression of classical peptidases which are directly involved in the Leishmania pathogenesis. All the HIV PIs impaired parasite growth in a dose-dependent fashion, especially nelfinavir and lopinavir. HIV PIs treatment caused profound changes in the leishmania ultrastructure as shown by transmission electron microscopy, including cytoplasm shrinking, increase in the number of lipid inclusions and some cells presenting the nucleus closely wrapped by endoplasmic reticulum resembling an autophagic process, as well as chromatin condensation which is suggestive of apoptotic death. The hydrolysis of HIV peptidase substrate by L. amazonensis extract was inhibited by pepstatin and HIV PIs, suggesting that an aspartyl peptidase may be the intracellular target of the inhibitors. The treatment with HIV PIs of either the promastigote forms preceding the interaction with macrophage cells or the amastigote forms inside macrophages drastically reduced the association indexes. Despite all these beneficial effects, the HIV PIs induced an increase in the expression of cysteine peptidase b (cpb) and the metallopeptidase gp63, two well-known virulence factors expressed by Leishmania spp. CONCLUSIONS/SIGNIFICANCE: In the face of leishmaniasis/HIV overlap, it is critical to further comprehend the sophisticated interplays among Leishmania, HIV and macrophages. In addition, there are many unresolved questions related to the management of Leishmania-HIV-coinfected patients. For instance, the efficacy of therapy aimed at controlling each pathogen in coinfected individuals remains largely undefined. The results presented herein add new in vitro insight into the wide spectrum efficacy of HIV PIs and suggest that additional studies about the synergistic effects of classical antileishmanial compounds and HIV PIs in macrophages coinfected with Leishmania and HIV-1 should be performed.
PMID: 19325703 [PubMed - in process]
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Related Articles
- Beneficial effects of HIV peptidase inhibitors on Fonsecaea pedrosoi: promising compounds to arrest key fungal biological processes and virulence. [PLoS ONE. 2008]
- Review[Highly Active AntiRetroviral Therapy and opportunistic protozoan infections] [Parassitologia. 2004]
- Intracellular survival of Leishmania species that cause visceral leishmaniasis is significantly reduced by HIV-1 protease inhibitors. [J Infect Dis. 2008]
- ReviewLopinavir/ritonavir: a review of its use in the management of HIV infection. [Drugs. 2003]
- Darunavir: A Review of its Use in the Management of HIV Infection in Adults. [Drugs. 2009]
- Patient Drug Information
- Nelfinavir (Viracept® ) Nelfinavir is used in combination with other medications to treat human immunodeficiency virus (HIV) infection in patients with or without acquired immunodeficiency syndrome (AIDS). Nelfinavir is one of a class of medica...
Source: AHFS Consumer Medication Information -
- 2: J Biol Chem. 2009 Mar 26. [Epub ahead of print]
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Membrane permeabilization by trypanosome lytic factor, a cytolytic human high-density lipoprotein.
Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602.
Trypanosome lytic factor (TLF) is a subclass of human high-density lipoprotein (HDL) that mediates an innate immune killing of certain mammalian trypanosomes, most notably Trypanosoma brucei brucei, the causative agent of a wasting disease in cattle. Mechanistically, killing is initiated in the lysosome of the target trypanosome where the acidic pH facilitates a membrane disrupting activity by TLF. Here we utilize a model liposome system to characterize the membrane binding and permeabilizing activity of TLF and its protein constituents, haptoglobin related protein (Hpr), apolipoprotein L-1 (apoL-1) and apolipoprotein A-1 (apoA-1). We show that TLF efficiently binds and permeabilizes unilamellar liposomes at lysosomal pH whereas non-lytic human HDL exhibits inefficient permeabilizing activity. Purified, delipidated Hpr and apoL-1 both efficiently permeabilize lipid bilayers at low pH. Trypanosome lytic factor, apoL-1 and apoA-1 exhibit specificity for anionic membranes while Hpr permeabilizes both anionic and zwitterionic membranes. Analysis of the relative particle sizes of susceptible liposomes reveals distinctly different membrane-active behavior for native TLF and the delipidated protein components. We propose that lysosomal membrane damage in TLF susceptible trypanosomes is initiated by the stable association of the TLF particle with the lysosomal membrane and that this is a property unique to this subclass of human HDL.
PMID: 19324878 [PubMed - as supplied by publisher]
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- Serum resistance-associated protein blocks lysosomal targeting of trypanosome lytic factor in Trypanosoma brucei. [Eukaryot Cell. 2006]
- Haptoglobin-related protein mediates trypanosome lytic factor binding to trypanosomes. [J Biol Chem. 2001]
- African trypanosomes: intracellular trafficking of host defense molecules. [J Eukaryot Microbiol. 2007]
- ReviewMutual self-defence: the trypanolytic factor story. [Microbes Infect. 2008]
- ReviewTrypanosome lytic factors: novel mediators of human innate immunity. [Curr Opin Microbiol. 2001]
- Patient Drug Information
- Daunorubicin (Cerubidine® , DaunoXome® ) Your doctor has ordered the drug daunorubicin to help treat your illness. The drug is given by injection into a vein.
- Doxorubicin (Adriamycin PFS® , Adriamycin RDF® , Adriamycin® , ...) Your doctor has ordered the drug doxorubicin to help treat your illness. The drug is given by injection into a vein.
Source: AHFS Consumer Medication Information -
- 3: Bioorg Med Chem. 2009 Jan 15;17(2):641-52. Epub 2008 Dec 3.
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Synthesis, trypanocidal activity and docking studies of novel quinoxaline-N-acylhydrazones, designed as cruzain inhibitors candidates.
Laboratório de Avaliação e Síntese de Substâncias Bioativas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, PO Box 68024, RJ 21944-970, Brazil.
In this paper, we report the structural design, synthesis, trypanocidal activity and docking studies of novel quinoxaline-N-acylhydrazone (NAH) derivatives, planned as cruzain inhibitors candidates, a cysteine protease essential for the survival of Trypanosoma cruzi within the host cell. The salicylaldehyde N-acylhydrazones 7a and 8a presented IC(50) values of the same magnitude order than the standard drug nifurtimox (Nfx), when tested in vitro against epimastigote forms of Trypanosoma cruzi (Tulahuen 2 strain) and were non-toxic at the highest assayed doses rendering selectivity indexes (IC(50) (macrophages)/IC(50) (Trypanosoma cruzi)) of >25 for 7a and >20 for 8a, with IC(50) values in macrophages >400 microM.
PMID: 19110434 [PubMed - indexed for MEDLINE]
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- Synthesis, Cruzain docking, and in vitro studies of aryl-4-oxothiazolylhydrazones against Trypanosoma cruzi. [ChemMedChem. 2007]
- Potent second generation vinyl sulfonamide inhibitors of the trypanosomal cysteine protease cruzain. [Bioorg Med Chem Lett. 2001]
- Quinoxaline N,N'-dioxide derivatives and related compounds as growth inhibitors of Trypanosoma cruzi. Structure-activity relationships. [Bioorg Med Chem Lett. 2004]
- Review[The chemotherapy of Chagas disease] [Medicina (B Aires). 1999]
- ReviewCysteine proteinases of trypanosome parasites: novel targets for chemotherapy. [Curr Drug Targets. 2000]
- 4: Bioorg Med Chem. 2009 Jan 15;17(2):741-51. Epub 2008 Nov 25.
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Synthesis and evaluation of dihydroartemisinin and dihydroartemisitene acetal dimers showing anticancer and antiprotozoal activity.
National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA. amgalalv@olemiss.edu
Twelve artemisinin acetal dimers were synthesized and tested for antitumor activity in the National Cancer Institute (NCI) in vitro human tumor 60 cell line assay, producing a mean GI(50) concentration between 8.7 (least active) and 0.019 microM (most active). The significant activity of the compounds in this preliminary screen led to additional in vitro antitumor and antiangiogenesis studies. Several active dimers were also evaluated in the in vivo NCI hollow fiber assay followed by a preliminary xenograft study. The title compounds were found to be active against solid tumor-derived cell lines and showed good correlation with other artemisinin-based molecules in the NCI database. The dimers were also evaluated for their antimalarial and antileishmanial activities. The antimalarial activity ranged from 0.3 to 32 nM (IC(50)), compared to 9.9 nM for artemisinin.
PMID: 19084416 [PubMed - indexed for MEDLINE]
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- Antimalarial and antitumor evaluation of novel C-10 non-acetal dimers of 10beta-(2-hydroxyethyl)deoxoartemisinin. [J Med Chem. 2004]
- Antimalarial, antiproliferative, and antitumor activities of artemisinin-derived, chemically robust, trioxane dimers. [J Med Chem. 1999]
- Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents. [J Med Chem. 2004]
- ReviewRecent advances in artemisinin and its derivatives as antimalarial and antitumor agents. [Curr Med Chem. 2004]
- ReviewAntiprotozoal lysophospholipid analogues: a comparison of their activity against trypanosomatid parasites and tumor cells. [Mini Rev Med Chem. 2004]
- 5: Toxicology. 2009 Jan 8;255(1-2):72-9. Epub 2008 Oct 25.
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Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy.
TopoTarget A/S, Symbion Science Park, Fruebjergvej 3, Copenhagen 2100, Denmark.
Anthracycline-induced cardiomyopathy is a major problem in anti-cancer therapy. The only approved agent for alleviating this serious dose limiting side effect is ICRF-187 (dexrazoxane). The current thinking is that the ring-opened hydrolysis product of this agent, ADR-925, which is formed inside cardiomyocytes, removes iron from its complexes with anthracyclines, hereby reducing the concentration of highly toxic iron-anthracycline complexes that damage cardiomyocytes by semiquinone redox recycling and the production of free radicals. However, the 2 carbon linker ICRF-187 is also is a catalytic inhibitor of topoisomerase II, resulting in the risk of additional myelosuppression in patients receiving ICRF-187 as a cardioprotectant in combination with doxorubicin. The development of a topoisomerase II-inactive iron chelating compound thus appeared attractive. In the present paper we evaluate the topoisomerase II-inactive 3 carbon linker bisdioxopiperazine analog ICRF-161 as a cardioprotectant. We demonstrate that this compound does chelate iron and protects against doxorubicin-induced LDH release from primary rat cardiomyocytes in vitro, similarly to ICRF-187. The compound does not target topoisomerase II in vitro or in cells, it is well tolerated and shows similar exposure to ICRF-187 in rodents, and it does not induce myelosuppression when given at high doses to mice as opposed to ICRF-187. However, when tested in a model of chronic anthracycline-induced cardiomyopathy in spontaneously hypertensive rats, ICRF-161 was not capable of protecting against the cardiotoxic effects of doxorubicin. Modulation of the activity of the beta isoform of the topoisomerase II enzyme by ICRF-187 has recently been proposed as the mechanism behind its cardioprotection. This concept is thus supported by the present study in that iron chelation alone does not appear to be sufficient for protection against anthracycline-induced cardiomyopathy.
PMID: 19010377 [PubMed - indexed for MEDLINE]
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- Comparison of the protective effects against chronic doxorubicin cardiotoxicity and the rates of iron (III) displacement reactions of ICRF-187 and other bisdiketopiperazines. [Cancer Chemother Pharmacol. 1997]
- Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. [Cancer Res. 2007]
- ICRF-187 rescue in etoposide treatment in vivo. A model targeting high-dose topoisomerase II poisons to CNS tumors. [Cancer Chemother Pharmacol. 1996]
- Review[Dexrazoxane (ICRF-187)--a cardioprotectant and modulator of action of some anticancer drugs] [Postepy Hig Med Dosw (Online). 2006]
- ReviewDexrazoxane (ICRF-187). [Gen Pharmacol. 1999]
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