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  • Journal article
    Saunders CN, Cota E, Baum J, Tate EWet al., 2020,

    Peptide probes for Plasmodium falciparum MyoA tail interacting protein (MTIP): exploring the druggability of the malaria parasite motor complex

    , ACS Chemical Biology, Vol: 15, Pages: 1313-1320, ISSN: 1554-8929

    Malaria remains an endemic tropical disease, and the emergence of Plasmodium falciparum parasites resistant to current front-line medicines means that new therapeutic targets are required. The Plasmodium glideosome is a multiprotein complex thought to be essential for efficient host red blood cell invasion. At its core is a myosin motor, Myosin A (MyoA), which provides most of the force required for parasite invasion. Here, we report the design and development of improved peptide-based probes for the anchor point of MyoA, the P. falciparum MyoA tail interacting protein (PfMTIP). These probes combine low nanomolar binding affinity with significantly enhanced cell penetration and demonstrable competitive target engagement with native PfMTIP through a combination of Western blot and chemical proteomics. These results provide new insights into the potential druggability of the MTIP/MyoA interaction and a basis for the future design of inhibitors.

  • Journal article
    Simoes BM, Santiago-Gomez A, Chiodo C, Moreira T, Conole D, Lovell S, Alferez D, Eyre R, Spence K, Sarmiento-Castro A, Kohler B, Morisset L, Lanzino M, Ando S, Marangoni E, Sims AH, Tate EW, Howell SJ, Clarke RBet al., 2020,

    Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

    , ONCOGENE, Vol: 39, Pages: 4896-4908, ISSN: 0950-9232
  • Journal article
    Fedoryshchak R, Ocasio C, Strutton B, Mattocks J, Corran A, Tate Eet al., 2020,

    Wheat pathogen Zymoseptoria tritici N-myristoyltransferase inhibitors: on-target antifungal activity and an unusual metabolic defense mechanism

    , RSC Chemical Biology, Vol: 1, Pages: 68-78, ISSN: 1747-1613

    Zymoseptoria tritici is the causative agent of Septoria tritici blotch (STB), which costs billions of dollars annually to major wheat-producing countries in terms of both fungicide use and crop loss. Agricultural pathogenic fungi have acquired resistance to most commercially available fungicide classes, and the rate of discovery and development of new fungicides has stalled, demanding new approaches and insights. Here we investigate a potential mechanism of targeting an important wheat pathogen Z. tritici via inhibition of N-myristoyltransferase (NMT). We characterize Z. tritici NMT biochemically for the first time, profile the in vivo Z. tritici myristoylated proteome and identify and validate the first Z. tritici NMT inhibitors. Proteomic investigation of the downstream effects of NMT inhibition identified an unusual and novel mechanism of defense against chemical toxicity in Z. tritici through the application of comparative bioinformatics to deconvolute function from the previously largely unannotated Z. tritici proteome. Research into novel fungicidal modes-of-action is essential to satisfy an urgent unmet need for novel fungicide targets, and we anticipate that this study will serve as a useful proteomics and bioinformatics resource for researchers studying Z. tritici.

  • Journal article
    Anderson DP, Benns HJ, Tate EW, Child MAet al., 2020,

    CRISPR-TAPE: protein-centricCRISPRguide design for targeted proteome engineering

    , MOLECULAR SYSTEMS BIOLOGY, Vol: 16, ISSN: 1744-4292
  • Journal article
    Shchepinova MM, Hanyaloglu AC, Frost GS, Tate EWet al., 2020,

    Chemical biology of noncanonical G protein-coupled receptor signaling: Toward advanced therapeutics

    , CURRENT OPINION IN CHEMICAL BIOLOGY, Vol: 56, Pages: 98-110, ISSN: 1367-5931
  • Journal article
    de Chiara C, Homsak M, Prosser GA, Douglas HL, Garza-Garcia A, Kelly G, Purkiss AG, Tate EW, de Carvalho LPSet al., 2020,

    D-Cycloserine destruction by alanine racemase and the limit of irreversible inhibition

    , NATURE CHEMICAL BIOLOGY, Vol: 16, Pages: 686-+, ISSN: 1552-4450
  • Journal article
    Anderson DP, Benns HJ, Tate EW, Child MAet al., 2020,

    CRISPR-TAPE: protein-centric CRISPR guide design for targeted proteome engineering.

    , Mol Syst Biol, Vol: 16

    Rational molecular engineering of proteins with CRISPR-based approaches is challenged by the gene-centric nature of gRNA design tools. To address this, we have developed CRISPR-TAPE, a protein-centric gRNA design algorithm that allows users to target specific residues, or amino acid types within proteins. gRNA outputs can be customized to support maximal efficacy of homology-directed repair for engineering purposes, removing time-consuming post hoc curation, simplifying gRNA outputs and reducing CPU times.

  • Journal article
    Kounde C, Shchepinova M, Saunders C, Muelbaier M, Rackham M, Harling J, Tate Eet al., 2020,

    A caged E3 ligase ligand for PROTAC-mediated protein degradation with light

    , Chemical Communications, Vol: 56, Pages: 5532-5535, ISSN: 1359-7345

    With the intent of achieving greater spatiotemporal control of PROTAC-induced protein degradation, a light-activated degrader was designed by photocaging an essential E3 ligase binding motif in a BRD4 targeting PROTAC. Proteolysis was triggered only after a short irradiation time, the kinetics of which could be monitored by live-cell video microscopy.

  • Journal article
    Ward JA, Pinto-Fernandez A, Cornelissen L, Bonham S, Diaz-Saez L, Riant O, Huber KVM, Kessler BM, Feron O, Tate EWet al., 2020,

    Re-Evaluating the Mechanism of Action of alpha,beta-Unsaturated Carbonyl DUB Inhibitors b-AP15 and VLX1570: A Paradigmatic Example of Unspecific Protein Cross-linking with Michael Acceptor Motif-Containing Drugs

    , JOURNAL OF MEDICINAL CHEMISTRY, Vol: 63, Pages: 3756-3762, ISSN: 0022-2623
  • Journal article
    Tzakoniati F, Xu H, Garcia N, Kugel C, Payandeh J, Koth CM, Tate Eet al., 2020,

    Development of photocrosslinking probes based on Huwentoxin-IV to map the site of interaction on Nav1.7

    , Cell Chemical Biology, Vol: 27, Pages: 306-313.e4, ISSN: 2451-9456

    Voltage-gated sodium (Nav) channels respond to changes in the membrane potential of excitable cells through the concerted action of four voltage-sensor domains (VSDs). Subtype Nav1.7 plays an important role in the propagation of signals in pain-sensing neurons and is a target for the clinical development of novel analgesics. Certain inhibitory cystine knot (ICK) peptides produced by venomous animals potently modulate Nav1.7, however the molecular mechanisms underlying their selective binding and activity remain elusive. This study reports on the design of a library of photoprobes based on the potent spider toxin Huwentoxin-IV and the determination of the toxin binding interface on VSD2 of Nav1.7 through a photocrosslinking and tandem mass spectrometry approach. Our Huwentoxin-IV probes selectively crosslink to extracellular loop S1-2 and helix S3 of VSD2 in a chimeric channel system. Our results provide a strategy that will enable mapping of sites of interaction of other ICK peptides on Nav channels.

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Contact

Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821