ORCID Profile
0000-0001-5574-3766
Current Organisation
University of York
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Publisher: Springer Science and Business Media LLC
Date: 02-09-2010
Publisher: American Association for the Advancement of Science (AAAS)
Date: 15-01-2005
Abstract: Leishmania species cause a spectrum of human diseases in tropical and subtropical regions of the world. We have sequenced the 36 chromosomes of the 32.8-megabase haploid genome of Leishmania major (Friedlin strain) and predict 911 RNA genes, 39 pseudogenes, and 8272 protein-coding genes, of which 36% can be ascribed a putative function. These include genes involved in host-pathogen interactions, such as proteolytic enzymes, and extensive machinery for synthesis of complex surface glycoconjugates. The organization of protein-coding genes into long, strand-specific, polycistronic clusters and lack of general transcription factors in the L. major, Trypanosoma brucei , and Trypanosoma cruzi (Tritryp) genomes suggest that the mechanisms regulating RNA polymerase IIâdirected transcription are distinct from those operating in other eukaryotes, although the trypanosomatids appear capable of chromatin remodeling. Abundant RNA-binding proteins are encoded in the Tritryp genomes, consistent with active posttranscriptional regulation of gene expression.
Publisher: Elsevier BV
Date: 06-2000
DOI: 10.1016/S1074-5521(00)00124-1
Abstract: Chemical inhibitors of cyclin-dependent kinases (CDKs) have great therapeutic potential against various proliferative and neurodegenerative disorders. Olomoucine, a 2,6,9-trisubstituted purine, has been optimized for activity against CDK1/cyclin B by combinatorial and medicinal chemistry efforts to yield the purvalanol inhibitors. Although many studies support the action of purvalanols against CDKs, the actual intracellular targets of 2,6, 9-trisubstituted purines remain unverified. To address this issue, purvalanol B (95. ) and an N6-methylated, CDK-inactive derivative (95M. ) were immobilized on an agarose matrix. Extracts from a erse collection of cell types and organisms were screened for proteins binding purvalanol B. In addition to validating CDKs as intracellular targets, a variety of unexpected protein kinases were recovered from the 95. matrix. Casein kinase 1 (CK1) was identified as a principal 95. matrix binding protein in Plasmodium falciparum, Leishmania mexicana, Toxoplasma gondii and Trypanosoma cruzi. Purvalanol compounds also inhibit the proliferation of these parasites, suggesting that CK1 is a valuable target for further screening with 2,6,9-trisubstituted purine libraries. That a simple batchwise affinity chromatography approach using two purine derivatives facilitated isolation of a small set of highly purified kinases suggests that this could be a general method for identifying intracellular targets relevant to a particular class of ligands. This method allows a close correlation to be established between the pattern of proteins bound to a small family of related compounds and the pattern of cellular responses to these compounds.
Publisher: Public Library of Science (PLoS)
Date: 13-06-2017
Publisher: Wiley
Date: 09-08-2007
DOI: 10.1016/J.FEBSLET.2007.07.072
Abstract: The physiological significance of the squamous cell carcinoma antigens 1 (SCCA1) and SCCA2, members of the ovalbumin serpin family, remains unresolved. In this study, we examined whether SCCA1 or SCCA2 inhibits protozoa- or helminth-derived cysteine proteases. SCCA1, but not SCCA2, potently inhibited the cysteine protease activities of CPB2.8 from Leishmania mexicana, cruzain from Trypanosoma cruzi, rhodesain from Trypanosoma brucei rhodesience, and cathepsin L2 from Fasciola hepatica. The inhibitory activities of SCCA1 were due to its resistance to cleavage by the cysteine proteases. The findings indicate that induction of cysteine protease inhibitors might be a novel defense mechanism against parasite development.
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.4161/AUTO.19496
Publisher: Informa UK Limited
Date: 02-01-2016
Publisher: Elsevier BV
Date: 08-2002
DOI: 10.1016/S1471-4922(02)02321-8
Abstract: The importance of protein kinases in cell signaling and cell cycle control has led to detailed structural and functional studies in various eukaryotes, and hence to the synthesis of specific chemical inhibitors for managing disease. Here, the current progress in applying developments from the wider protein kinase field to parasitic protozoa is reviewed. The availability of genome sequence data for several parasites has led to the identification of many protein kinases. Reverse genetics studies, including gene knockout and 'chemical genetics', can help to define the roles of the protein kinases and validate them as drug targets. In addition, screening chemical libraries with active recombinant protein kinases can identify lead compounds for drug design.
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Jeremy Mottram.