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  • Journal article
    Kalesh KA, Tate EW, 2014,

    A succinyl lysine-based photo-cross-linking peptide probe for Sirtuin 5

    , ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 12, Pages: 4310-4313, ISSN: 1477-0520
  • Journal article
    Brannigan JA, Roberts SM, Bell AS, Hutton JA, Hodgkinson MR, Tate EW, Leatherbarrow RJ, Smith DF, Wilkinson AJet al., 2014,

    Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors

    , IUCrJ, Vol: 1, Pages: 250-260, ISSN: 2052-2525

    The leishmaniases are a spectrum of global diseases of poverty associated withimmune dysfunction and are the cause of high morbidity. Despite the longhistory of these diseases, no effective vaccine is available and the currently useddrugs are variously compromised by moderate efficacy, complex side effects andthe emergence of resistance. It is therefore widely accepted that new therapiesare needed. N-Myristoyltransferase (NMT) has been validated pre-clinically asa target for the treatment of fungal and parasitic infections. In a previouslyreported high-throughput screening program, a number of hit compounds withactivity against NMT from Leishmania donovani have been identified. Here,high-resolution crystal structures of representative compounds from four hitseries in ternary complexes with myristoyl-CoA and NMT from the closelyrelated L. major are reported. The structures reveal that the inhibitors associatewith the peptide-binding groove at a site adjacent to the bound myristoyl-CoAand the catalytic -carboxylate of Leu421. Each inhibitor makes extensiveapolar contacts as well as a small number of polar contacts with the protein.Remarkably, the compounds exploit different features of the peptide-bindinggroove and collectively occupy a substantial volume of this pocket, suggestingthat there is potential for the design of chimaeric inhibitors with significantlyenhanced binding. Despite the high conservation of the active sites of theparasite and human NMTs, the inhibitors act selectively over the host enzyme.The role of conformational flexibility in the side chain of Tyr217 in conferringselectivity is discussed.

  • Journal article
    Gray K, Elghadban S, Thongyoo P, Owen KA, Szabo R, Bugge TH, Tate EW, Leatherbarrow RJ, Ellis Vet al., 2014,

    Potent and specific inhibition of the biological activity of the type-II transmembrane serine protease matriptase by the cyclic microprotein MCoTI-II

    , Thrombosis and Haemostasis, Vol: 112, Pages: 402-411, ISSN: 0340-6245

    Matriptase is a type-II transmembrane serine protease involved in epithelial homeostasis in both health and disease, and is implicated in the development and progression of a variety of cancers. Matriptase mediates its biological effects both via as yet undefined substrates and pathways, and also by proteolytic cleavage of a variety of well-defined protein substrates, several of which it shares with the closely-related protease hepsin. Development of targeted therapeutic strategies will require discrimination between these proteases. Here we have investigated cyclic microproteins of the squash Momordica cochinchinensis trypsin-inhibitor family (generated by total chemical synthesis) and found MCoTI-II to be a high-affinity (Ki 9 nM) and highly selective (> 1,000-fold) inhibitor of matriptase. MCoTI-II efficiently inhibited the proteolytic activation of pro-hepatocyte growth factor (HGF) by matriptase but not by hepsin, in both purified and cell-based systems, and inhibited HGF-dependent cell scattering. MCoTI-II also selectively inhibited the invasion of matriptase-expressing prostate cancer cells. Using a model of epithelial cell tight junction assembly, we also found that MCoTI-II could effectively inhibit the re-establishment of tight junctions and epithelial barrier function in MDCK-I cells after disruption, consistent with the role of matriptase in regulating epithelial integrity. Surprisingly, MCoTI-II was unable to inhibit matriptase-dependent proteolytic activation of prostasin, a GPI-anchored serine protease also implicated in epithelial homeostasis. These observations suggest that the unusually high selectivity afforded by MCoTI-II and its biological effectiveness might represent a useful starting point for the development of therapeutic inhibitors, and further highlight the role of matriptase in epithelial maintenance.

  • Conference paper
    Bell AS, Goncalves V, Hutton JA, Waugh TM, Wright MH, Yu Z, Brannigan JA, Paape D, Leatherbarrow RJ, Tate EW, Wilkinson AJ, Smith DFet al., 2014,

    <i>N</i>-Myristoyltransferase inhibitors as anti-leishmanial agents

    , 247th National Spring Meeting of the American-Chemical-Society (ACS), Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727
  • Journal article
    Konitsiotis AD, Chang S-C, Jovanovic B, Ciepla P, Masumoto N, Palmer CP, Tate EW, Couchman JR, Magee AIet al., 2014,

    Attenuation of Hedgehog Acyltransferase-Catalyzed Sonic Hedgehog Palmitoylation Causes Reduced Signaling, Proliferation and Invasiveness of Human Carcinoma Cells

    , PLOS ONE, Vol: 9, ISSN: 1932-6203
  • Journal article
    Rackham MD, Brannigan JA, Rangachari K, Meister S, Wilkinson AJ, Holder AA, Leatherbarrow RJ, Tate EWet al., 2014,

    Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)

    , Journal of Medicinal Chemistry, Vol: 57, Pages: 2773-2788, ISSN: 0022-2623

    N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasiticinfections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT anddisplays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of apreviously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of lessthan 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavyatoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage formsof the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool forfurther optimization.

  • Journal article
    Wright MH, Clough B, Rackham MD, Kaveri R, Brannigan J, Grainger M, Moss DK, Bottrill AR, Heal WP, Broncel M, Serwa RA, Brady D, Mann DJ, Leatherbarrow RJ, Tewari R, Wilkinson AJ, Holder AA, Tate EWet al., 2013,

    Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

    , Nature Chemistry, Vol: 6, Pages: 112-121, ISSN: 1755-4349

    Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase.

  • Journal article
    Poulin B, Patzewitz E-M, Brady D, Silvie O, Wright MH, Ferguson DJP, Wall RJ, Whipple S, Guttery DS, Tate EW, Wickstead B, Holder AA, Tewari Ret al., 2013,

    Unique apicomplexan IMC sub-compartment proteins are early markers for apical polarity in the malaria parasite

    , Biology Open, Vol: 2, Pages: 1160-1170, ISSN: 2046-6390

    The phylum Apicomplexa comprises over 5000 intracellularprotozoan parasites, including Plasmodium and Toxoplasma,that are clinically important pathogens affecting humans andlivestock. Malaria parasites belonging to the genusPlasmodium possess a pellicle comprised of a plasmalemmaand inner membrane complex (IMC), which is implicated inparasite motility and invasion. Using live cell imaging andreverse genetics in the rodent malaria model P. berghei, welocalise two unique IMC sub-compartment proteins (ISPs)and examine their role in defining apical polarity duringzygote (ookinete) development. We show that these proteinslocalise to the anterior apical end of the parasite where IMCorganisation is initiated, and are expressed at alldevelopmental stages, especially those that are invasive.Both ISP proteins are N-myristoylated, phosphorylated andmembrane-bound. Gene disruption studies suggest that ISP1is likely essential for parasite development, whereas ISP3 isnot. However, an absence of ISP3 alters the apical localisationof ISP1 in all invasive stages including ookinetes andsporozoites, suggesting a coordinated function for theseproteins in the organisation of apical polarity in the parasite.

  • Journal article
    Alibhai D, Kelly DJ, Warren S, Kumar S, Margineau A, Serwa RA, Thinon E, Alexandrov Y, Murray EJ, Stuhmeier F, Tate EW, Neil MAA, Dunsby C, French PMWet al., 2013,

    Automated fluorescence lifetime imaging plate reader and its application to Forster resonant energy transfer readout of Gag protein aggregation

    , Journal of Biophotonics, Vol: 6, Pages: 398-408, ISSN: 1864-0648

    Fluorescence lifetime measurements can provide quantitativereadouts of local fluorophore environment andcan be applied to biomolecular interactions via Fo¨ rsterresonant energy transfer (FRET). Fluorescence lifetimeimaging (FLIM) can therefore provide a high contentanalysis (HCA) modality to map protein-protein interactions(PPIs) with applications in drug discovery, systemsbiology and basic research. We present here an automatedmultiwell plate reader able to perform rapid unsupervisedoptically sectioned FLIM of fixed and livebiological samples and illustrate its potential to assayPPIs through application to Gag protein aggregationduring the HIV life cycle. We demonstrate both heteroFRETand homo-FRET readouts of protein aggregationand report the first quantitative evaluation of a FLIMHCA assay by generating dose response curves throughaddition of an inhibitor of Gag myristoylation. Z0 factorsexceeding 0.6 are realised for this FLIM FRET assay.Fluorescence lifetime plate map with representativeimages of high and low FRET cells and correspondingdose response plot.

  • Journal article
    Tate EW, Bell AS, Rackham MD, Wright AHet al., 2013,

    N- Myristoyltransferase as a potential drug target in malaria and leishmaniasis

    , Parasitology, Vol: 141, Pages: 37-49, ISSN: 1469-8161

    Infections caused by protozoan parasites are among the most widespread and intractable transmissible diseases affecting the developing world, with malaria and leishmaniasis being the most costly in terms of morbidity and mortality. Although new drugs are urgently required against both diseases in the face of ever-rising resistance to frontline therapies, very few candidates passing through development pipelines possess a known and novel mode of action. Set in the context of drugs currently in use and under development, we present the evidence for N-myristoyltransferase (NMT), an enzyme that N-terminally lipidates a wide range of specific target proteins through post-translational modification, as a potential drug target in malaria and the leishmaniases. We discuss the limitations of current knowledge regarding the downstream targets of this enzyme in protozoa, and our recent progress towards potent cell-active NMT inhibitors against the most clinically-relevant species of parasite. Finally, we outline the next steps required in terms of both tools to understand N-myristoylation in protozoan parasites, and the generation of potential development candidates based on the output of our recently-reported high-throughput screens.

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