What's new for 'Trypanosomatids' in PubMed

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Sent on Saturday, 2011 Dec 03
Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results

Items 1 - 3 of 3

1.	J Lipid Res. 2011 Nov 30. [Epub ahead of print] Structural complex of sterol 14α-demethylase (CYP51) with 14α-methylenecyclopropyl-{Delta}7-24, 25-dihydrolanosterol. Hargrove TY, Wawrzak Z, Liu J, Waterman MR, Nes WD, Lepesheva GI. Source Vanderbilt University School of Medicine, United States; Abstract Sterol 14α-demethylase (CYP51) that catalyzes the removal of the 14α-methyl group from the sterol nucleus is an essential enzyme in sterol biosynthesis, a primary target for clinical and agricultural antifungal azoles and an emerging target for anti-trypanosomal chemotherapy. Here, we present the crystal structure of Trypanosoma (T) brucei CYP51 in complex with the substrate analog 14α-methylenecyclopropyl-Δ7-24,25-dihydrolanosterol (MCP). This sterol binds tightly to all protozoan CYP51s, acts as a competitive inhibitor of F105-containing (plant-like) T. brucei and Leishmania infantum orthologs, but has a much stronger, mechanism-based inhibitory effect on I105-containing (animal/fungi-like) T. cruzi CYP51. Depicting substrate orientation in the conserved CYP51 binding cavity, the complex specifies the roles of the contact amino acid residues and sheds new light on CYP51 substrate specificity. It also provides an explanation for the effect of MCP on T. cruzi CYP51. Comparison with the ligand-free and azole-bound structures supports the notion of structural rigidity as the characteristic feature of the CYP51 substrate binding cavity, confirming the enzyme as an excellent candidate for structure-directed design of new drugs including mechanism-based substrate analog inhibitors.
	PMID: 22135275 [PubMed - as supplied by publisher]

2.	Mol Pharm. 2011 Dec 1. [Epub ahead of print] Vaccination with Liposomal Leishmanial Antigens adjuvanted with MPL-TDM Confers Long-term Protection against Visceral Leishmaniasis through Human Adminstrable Route. Ravindran R, Maji M, Ali N. Abstract Development of long-term protective subunit vaccine against visceral leishmaniasis depends on antigens and adjuvants that can induce appropriate immune response. Immunization of leishmanial antigens alone show limited efficacy in absence of an appropriate adjuvant. Earlier we demonstrated sustained protection against Leishmania donovani with leishmanial antigens entrapped in cationic liposomes through intraperitoneal route. However, this route is not applicable for human adminstration. Herein, we therefore evaluated the immune response and protection induced by liposomal SLA formulated with MPL-TDM through subcutaneous route. Subcutaneous immunization of BALB/c mice with soluble leishmanial antigen (SLA) entrapped in liposomes or with MPL-TDM elicited partial protection against experimental visceral leishmaniasis. In contrast, liposomal SLA adjuvanted with MPL-TDM induced significantly higher levels of protection in liver and spleen in BALB/c mice challenged 10 days post vaccination. Protection conferred by this formulation was sustained upto 12 weeks of immunization and infection was controlled for at least 4 months of challenge, similar to liposomal SLA immunization administered intraperitoneally. Analysis of cellular immune responses of liposomal SLA+MPL-TDM immunized mice demonstrated induction of IFN-γ and IgG2a antibody production not only 10 days or 12 weeks post vaccination but also 4 months after challenge infection, and a down regulation of IL-4 production after infection. Moreover, long-term immunity elicited by this formulation was associated with IFN-γ production also by CD8+ T cells. Taken together, our results suggest that liposomal SLA+MPL-TDM represent a good vaccine formulation for induction of durable protection against L. donovani through human administrable route.
	PMID: 22133194 [PubMed - as supplied by publisher]

3.	Parasite Immunol. 2011 Dec 1. doi: 10.1111/j.1365-3024.2011.01347.x. [Epub ahead of print] Functional Genomics of Trypanosomatids. Choi J, El-Sayed NM. Source Department of Cell Biology and Molecular Genetics Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD 20742, USA. Abstract The decoding of the Tritryp reference genomes nearly seven years ago provided a first peek into the biology of pathogenic trypanosomatids and a blueprint that has paved the way for genome-wide studies. Although 60-70% of the predicted protein coding genes in Trypanosoma brucei, Trypanosoma cruzi and Leishmania major remain unannotated, the functional genomics landscape is rapidly changing. Facilitated by the advent of next-generation sequencing technologies, improved structural and functional annotation and genes and their products are emerging. Information is also growing for interactions between cellular components as transcriptomes, regulatory networks and metabolomes are characterized, ushering in a new era of systems biology. Simultaneously, the launch of comparative sequencing of multiple strains of kinetoplastids will finally lead to the investigation of a vast, yet to be explored, evolutionary and pathogenomic space. Copyright © 2011 Blackwell Publishing Ltd.
	PMID: 22132795 [PubMed - as supplied by publisher]