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  • Conference paper
    Konitsiotis A, Chang S, Masumoto N, Tate EW, Magee AIet al., 2012,

    Hhat a Potential New Target in Treatment of Pancreatic Cancer

    , 22nd Biennial Congress of the European-Association-for-Cancer-Research, Publisher: ELSEVIER SCI LTD, Pages: S149-S149, ISSN: 0959-8049
  • Journal article
    Bell AS, Mills JE, Williams GP, Brannigan JA, Wilkinson AJ, Parkinson T, Leatherbarrow RJ, Tate EW, Holder AA, Smith DFet al., 2012,

    Selective Inhibitors of Protozoan Protein N-myristoyltransferases as Starting Points for Tropical Disease Medicinal Chemistry Programs

    , PLOS Neglected Tropical Diseases, Vol: 6, ISSN: 1935-2735

    Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal andtrypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose toscreen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs.Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) andfor broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results hasshown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding notpredicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMTinhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting thatachieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series withselectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinctseries with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain willaccelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example ofhow a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/nongovernmentalorganisations such as Medical Research Council and Wellcome Trust can stimulate research for neglecteddiseases
  • Journal article
    Goncalves V, Brannigan JA, Whalley D, Ansell KH, Saxty B, Holder AA, Wilkinson AJ, Tate EW, Leatherbarrow RJet al., 2012,

    Discovery of Plasmodium vivax N-Myristoyltransferase Inhibitors: Screening, Synthesis, and Structural Characterization of their Binding Mode

    , Journal of Medicinal Chemistry, Vol: 55, Pages: 3578-3582, ISSN: 0022-2623

    N-Myristoyltransferase (NMT) is a prospective drug target against parasitic protozoa. Herein we report the successful discovery of a series of Plasmodium vivax NMT inhibitors by high-throughput screening. A high-resolution crystal structure of the hit compound in complex with NMT was obtained, allowing understanding of its novel binding mode. A set of analogues was designed and tested to define the chemical groups relevant for activity and selectivity.
  • Conference paper
    Bradshaw RT, Aronica PGA, Tate EW, Leatherbarrow RJ, Gould IRet al., 2012,

    Developing mutational locally enhanced sampling (MULES) for predicting relative binding free energies at protein-protein interfaces

    , 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS), Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727
  • Journal article
    Goncalves V, Brannigan JA, Thinon E, Olaleye TO, Serwa R, Lanzarone S, Wilkinson AJ, Tate EW, Leatherbarrow RJet al., 2012,

    A fluorescence-based assay for N-myristoyltransferase activity

    , Analytical Biochemistry, Vol: 421, Pages: 342-344, ISSN: 1096-0309

    N-myristoylation is the irreversible attachment of a C14 fatty acid, myristic acid, to the N-terminal glycine of a protein via formation of an amide bond. This modification is catalyzed by myristoyl–coenzyme A (CoA):protein N-myristoyltransferase (NMT), an enzyme ubiquitous in eukaryotes that is up-regulated in several cancers. Here we report a sensitive fluorescence-based assay to study the enzymatic activity of human NMT1 and NMT2 based on detection of CoA by 7-diethylamino-3-(4-maleimido-phenyl)-4-methylcoumarin. We also describe expression and characterization of NMT1 and NMT2 and assay validation with small molecule inhibitors. This assay should be broadly applicable to NMTs from a range of organisms.
  • Journal article
    Broncel M, Serwa RA, Tate EW, 2012,

    A New Chemical Handle for Protein AMPylation at the Host-Pathogen Interface

    , Chembiochem, Vol: 13, Pages: 183-185, ISSN: 1439-7633

    agging protein AMPylation: A new chemical reporter for AMPylation, recently identified as a key post-translational modification during bacterial infection, is a robust tool for detecting and identifying AMPylated proteins in vitro.
  • Journal article
    Dang THT, Fagan RP, Fairweather NF, Tate EWet al., 2012,

    Novel inhibitors of surface layer processing in Clostridium difficile

    , Bioorganic & Medicinal Chemistry, Vol: 20, Pages: 614-621, ISSN: 1464-3391

    Clostridium difficile, a leading cause of hospital-acquired bacterial infection, is coated in a dense surface layer (S-layer) that is thought to provide both physicochemical protection and a scaffold for host-pathogen interactions. The key structural components of the S-layer are two proteins derived from a polypeptide precursor, SlpA, via proteolytic cleavage by the protease Cwp84. Here, we report the design, synthesis and in vivo characterization of a panel of protease inhibitors and activity-based probes (ABPs) designed to target S-layer processing in live C. difficile cells. Inhibitors based on substrate-mimetic peptides bearing a C-terminal Michael acceptor warhead were found to be promising candidates for further development.
  • Journal article
    Heal WP, Wright MH, Thinon E, Tate EWet al., 2012,

    Multifunctional protein labeling via enzymatic N-terminal tagging and elaboration by click chemistry

    , NATURE PROTOCOLS, Vol: 7, Pages: 105-117, ISSN: 1754-2189
  • Journal article
    Heal WP, Tate EW, 2012,

    Application of Activity-Based Protein Profiling to the Study of Microbial Pathogenesis

    , ACTIVITY-BASED PROTEIN PROFILING, Vol: 324, Pages: 115-135, ISSN: 0340-1022
  • Journal article
    Furse S, Brooks NJ, Seddon AM, Woscholski R, Templer RH, Tate EW, Gaffney PRJ, Ces Oet al., 2012,

    Lipid membrane curvature induced by distearoyl phosphatidylinositol 4-phosphate

    , Soft Matter

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