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  • Journal article
    Broncel M, Dominicus C, Vigetti L, Nofal SD, Bartlett EJ, Touquet B, Hunt A, Wallbank BA, Federico S, Matthews S, Young JC, Tate EW, Tardieux I, Treeck Met al., 2020,

    Profiling of myristoylation in Toxoplasma gondii reveals an N-myristoylated protein important for host cell penetration

    , ELIFE, Vol: 9, ISSN: 2050-084X
  • Journal article
    Maneiro M, Forte N, Shchepinova MM, Kounde CS, Chudasama V, Baker JR, Tate EWet al., 2020,

    Antibody–PROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4

    , ACS Chemical Biology, Vol: 15, Pages: 1306-1312, ISSN: 1554-8929

    Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although the high effectiveness of PROTACs against a wide variety of targets has been established, most degraders reported to date display limited intrinsic tissue selectivity and do not discriminate between cells of different types. Here, we describe a strategy for selective protein degradation in a specific cell type. We report the design and synthesis of a trastuzumab-PROTAC conjugate (Ab-PROTAC 3) in which E3 ligase-directed degrader activity is caged with an antibody linker which can be hydrolyzed following antibody–PROTAC internalization, releasing the active PROTAC and inducing catalytic protein degradation. We show that 3 selectively targets bromodomain-containing protein 4 (BRD4) for degradation only in HER2 positive breast cancer cell lines, while sparing HER2 negative cells. Using live cell confocal microscopy, we show internalization and lysosomal trafficking of the conjugate specifically in HER2 positive cells, leading to the release of active PROTAC in quantities sufficient to induce potent BRD4 degradation. These studies demonstrate proof-of-concept for tissue-specific BRD4 degradation, overcoming limitations of PROTAC selectivity, with significant potential for application to novel targets.

  • 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
    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
    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
    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

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