What's new for 'Trypanosomatids' in PubMed

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Sent on Wednesday, 2012 April 11
Search: kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"

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Items 1 - 3 of 3    (Display the 3 citations in PubMed)

1.	Chemistry. 2012 Apr 4. doi: 10.1002/chem.201103322. [Epub ahead of print] Design, Synthesis and Biological Evaluation of Potent Azadipeptide Nitrile Inhibitors and Activity-Based Probes as Promising Anti-Trypanosoma brucei Agents. Yang PY, Wang M, Li L, Wu H, He CY, Yao SQ. Source Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543 (Singapore), Fax: (+65) 6779-1691. Abstract Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas disease and African sleeping sickness, respectively. There is an urgent need for the development of new drugs against both diseases due to the lack of adequate cures and emerging drug resistance. One promising strategy for the discovery of small-molecule therapeutics against parasitic diseases has been to target the major cysteine proteases such as cruzain for T. cruzi, and rhodesain/TbCatB for T. brucei. Azadipeptide nitriles belong to a novel class of extremely potent cysteine protease inhibitors against papain-like proteases. We herein report the design, synthesis, and evaluation of a series of azanitrile-containing compounds, most of which were shown to potently inhibit both recombinant cruzain and rhodesain at low nanomolar/picomolar ranges. A strong correlation between the potency of rhodesain inhibition (i.e., target-based screening) and trypanocidal activity (i.e., whole-organism-based screening) of the compounds was observed. To facilitate detailed studies of this important class of inhibitors, selected hit compounds from our screenings were chemically converted into activity-based probes (ABPs), which were subsequently used for in situ proteome profiling and cellular localization studies to further elucidate potential cellular targets (on and off) in both the disease-relevant bloodstream form (BSF) and the insect-residing procyclic form (PCF) of Trypanosoma brucei. Overall, the inhibitors presented herein show great promise as a new class of anti-trypanosome agents, which possess better activities than existing drugs. The activity-based probes generated from this study could also serve as valuable tools for parasite-based proteome profiling studies, as well as bioimaging agents for studies of cellular uptake and distribution of these drug candidates. Our studies therefore provide a good starting point for further development of these azanitrile-containing compounds as potential anti-parasitic agents. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
	PMID: 22488888 [PubMed - as supplied by publisher]
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2.	Chem Biol Drug Des. 2012 Apr 5. doi: 10.1111/j.1747-0285.2012.01392.x. [Epub ahead of print] The Molecular Dynamics of Trypanosoma brucei UDP-Galactose 4'-Epimerase: A Drug Target for African Sleeping Sickness. Friedman AJ, Durrant JD, Pierce LC, McCorvie TJ, Timson DJ, McCammon JA. Source Biomedical Sciences Program, University of California San Diego, La Jolla, CA, 92093-0365 Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA, 92093-0365 School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, Belfast, BT9 7BL, UK Department of Chemistry & Biochemistry, NSF Center for Theoretical Biological Physics, National Biomedical Computation Resource, University of California San Diego, La Jolla, CA, 92093 Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093 Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92093. Abstract During the past century, several epidemics of human African trypanosomiasis, a deadly disease caused by the protist Trypanosoma brucei, have afflicted sub-Saharan Africa. Over 10,000 new victims are reported each year, with hundreds of thousands more at risk. As current drug treatments are either highly toxic or ineffective, novel trypanocides are urgently needed. The T. brucei galactose-synthesis pathway is one potential therapeutic target. Though galactose is essential for T. brucei survival, the parasite lacks the transporters required to intake galactose from the environment. UDP-galactose 4'-epimerase (TbGalE) is responsible for the epimerization of UDP-glucose to UDP-galactose and so is of great interest to medicinal chemists. Using molecular dynamics simulations, we investigate the atomistic motions of TbGalE in both the apo and holo states. The sampled conformations and protein dynamics depend not only on the presence of a UDP-sugar ligand, but also on the chirality of the UDP-sugar C4 atom. This dependence provides important insights into TbGalE function and may help guide future computer-aided drug-discovery efforts targeting this protein. © 2012 John Wiley & Sons A/S. © 2012 John Wiley & Sons A/S.
	PMID: 22487100 [PubMed - as supplied by publisher]
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3.	Cell Microbiol. 2012 Apr 10. doi: 10.1111/j.1462-5822.2012.01798.x. [Epub ahead of print] Ecotin-like serine peptidase inhibitor ISP1 of Leishmania major plays a role in flagellar pocket dynamics and promastigote differentiation. Morrison LS, Goundry A, Faria MS, Tetley L, Eschenlauer SC, Westrop GD, Dostalova A, Volf P, Coombs GH, Lima AP, Mottram JC. Source Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK. Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21949-900, Brazil. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK Charles University in Prague, Faculty of Science, Dep. Parasitology, Vinicna 7, Prague 2, CZ 128 44, Czech Republic. Abstract Leishmania ISPs are ecotin-like natural peptide inhibitors of trypsin-family serine peptidases, enzymes that are absent from the Leishmania genome. This led to the proposal that ISPs inhibit host serine peptidases and we have recently shown that ISP2 inhibits neutrophil elastase, thereby enhancing parasite survival in murine macrophages. In this study we show that ISP1 has less serine peptidase inhibitory activity than ISP2, and in promastigotes both are generally located in the cytosol and along the flagellum. However, in haptomonad promastigotes there is a prominent accumulation of ISP1 and ISP2 in the hemidesmosome and for ISP2 on the cell surface. An L. major mutant deficient in all three ISP genes (Δisp1/2/3) was generated and compared with Δisp2/3 mutants to elucidate the physiological role of ISP1. In in vitro cultures, the Δisp1/2/3 mutant contained more haptomonad, nectomonad and leptomonad promastigotes with elongated flagella and reduced motility compared with Δisp2/3, moreover it was characterised by very high levels of release of exosome-like vesicles from the flagellar pocket. These data suggest that ISP1 has a primary role in flagellar homeostasis, disruption of which affects differentiation, flagellar pocket dynamics and so interactions with the sand fly host. © 2012 Blackwell Publishing Ltd. © 2012 Blackwell Publishing Ltd.
	PMID: 22486816 [PubMed - as supplied by publisher]
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