What's new for 'Trypanosomatids' in PubMed

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Sent on Saturday, 2010 Nov 06
Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results

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1.	Bioorg Med Chem. 2010 Oct 8. [Epub ahead of print] Optimization of purine-nitrile TbcatB inhibitors for use in vivo and evaluation of efficacy in murine models. Mallari JP, Zhu F, Lemoff A, Kaiser M, Lu M, Brun R, Guy RK. Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco CA 94143-2280, United States; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis TN, 38105, United States. Abstract There are currently only four clinical drugs available for treating human African trypanosomiasis (HAT), three of which were developed over 60years ago. Despite years of effort, there has been relatively little progress towards identifying orally available chemotypes active against the parasite in vivo. Here, we report the lead optimization of a purine-nitrile scaffold that inhibits the essential TbcatB protease and its evaluation in murine models. A lead inhibitor that had potent activity against the trypanosomal protease TbcatB in vitro and cultured parasites ex vivo was optimized by rationally driven medicinal chemistry to an inhibitor that is orally available, penetrates the CNS, has a promising pharmacokinetic profile, and is non-toxic at 200mg/kg in a repeat dosage study. Efficacy models using oral administration of this lead inhibitor showed a significantly increased survival time in Trypanosoma brucei brucei infected mice but little effect on Trypanosoma brucei rhodesiense infected mice. Copyright © 2010 Elsevier Ltd. All rights reserved.
	PMID: 21051236 [PubMed - as supplied by publisher]
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2.	BMC Genomics. 2010 Nov 4;11(1):615. [Epub ahead of print] A comparative genome-wide study of ncRNAs in trypanosomatids. Doniger T, Katz R, Wachtel C, Michaeli S, Unger R. Abstract ABSTRACT: BACKGROUND: Recent studies have provided extensive evidence for multitudes of non-coding RNA (ncRNA) transcripts in a wide range of eukaryotic genomes. ncRNAs are emerging as key players in multiple layers of cellular regulation. With the availability of many whole genome sequences, comparative analysis has become a powerful tool to identify ncRNA molecules. In this study, we performed a systematic genome-wide in silico screen to search for novel small ncRNAs in the genome of Trypanosoma brucei using techniques of comparative genomics. RESULTS: In this study, we identified by comparative genomics, and validated by experimental analysis several novel ncRNAs that are conserved across multiple trypanosomatid genomes. When tested on known ncRNAs, our procedure was capable of finding almost half of the known repertoire through homology over six genomes, and about two-thirds of the known sequences were found in at least four genomes. After filtering, 72 conserved unannotated sequences in at least four genomes were found, 29 of which, ranging in size from 30 to 392 nts, were conserved in all six genomes. Fifty of the 72 candidates in the final set were chosen for experimental validation. Eighteen of the 50 (36%) were shown to be expressed, and for 11 of them a distinct expression product was detected, suggesting that they are short ncRNAs. Using functional experimental assays, five of the candidates were shown to be novel H/ACA and C/D snoRNAs; these included three sequences that appear as singletons in the genome, unlike previously identified snoRNA molecules that are found in clusters. The other candidates appear to be novel ncRNA molecules, and their function is, as yet, unknown. CONCLUSIONS: Using comparative genomic techniques, we predicted 72 sequences as ncRNA candidates in T. brucei. The expression of 50 candidates was tested in laboratory experiments. This resulted in the discovery of 11 novel short ncRNAs in procyclic stage T. brucei, which have homologues in the other trypansomatids. A few of these molecules are snoRNAs, but most of them are novel ncRNA molecules. Based on this study, our analysis suggests that the total number of ncRNAs in trypanosomatids is in the range of several hundred.
	PMID: 21050447 [PubMed - as supplied by publisher]
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3.	Adv Exp Med Biol. 2010;688:238-48. Sphingolipids in parasitic protozoa. Zhang K, Bangs JD, Beverley SM. Department of Biological Sciences, Texas Tech University, Lubbock, USA. Abstract The surface of most protozoan parasites relies heavily upon lipid-anchored molecules, to form protective barriers and play critical functions required for infectivity. Sphingolipids (SLs) play important roles through their abundance and involvement in membrane microdomain formation, as well as serving as the lipid anchor for many of these molecules and in some but possibly not all species, as important signaling molecules. Interactions of parasite sphingolipid metabolism with that of the host may potentially contribute to parasite survival and/or host defense. In this chapter we summarize current knowledge of SL structure, synthesis and function in several of the major parasitic protozoan groups. PMCID: PMC2951629 Free PMC Article
	PMID: 20919659 [PubMed - indexed for MEDLINE]
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