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  • Journal article
    Dubois MAJ, Lazaridou A, Choi C, Mousseau JJ, Bull JAet al., 2019,

    Synthesis of 3-Aryl-3-Sulfanyl Azetidines by Iron-Catalyzed Thiol Alkylation with N-Cbz Azetidinols

    , Journal of Organic Chemistry, Vol: 84, Pages: 5943-5956, ISSN: 0022-3263

    © 2019 American Chemical Society. New small-ring derivatives can provide valuable motifs in new chemical space for drug design. 3-Aryl-3-sulfanyl azetidines are synthesized directly from azetidine-3-ols in excellent yield by a mild Fe-catalyzed thiol alkylation. A broad range of thiols and azetidinols bearing electron-donating aromatics are successful, proceeding via an azetidine carbocation. The N-carboxybenzyl group is a requirement for good reactivity and enables the NH-azetidine to be revealed. Further reactions of the azetidine sulfides demonstrate their potential for incorporation in drug discovery programs.

  • Journal article
    Supramaniam P, Ces O, Salehi-Reyhani A, 2019,

    Microfluidics for Artificial Life: Techniques for Bottom-Up Synthetic Biology

    , MICROMACHINES, Vol: 10, ISSN: 2072-666X
  • Journal article
    Gilburt J, Girvan P, Blagg J, Ying L, Dodson CAet al., 2019,

    Ligand discrimination between active and inactive activation loop conformations of Aurora-A kinase is unmodified by phosphorylation

    , Chemical Science, Vol: 10, Pages: 4069-4076, ISSN: 2041-6520

    Structure-based drug design is commonly used to guide the development of potent and specific enzyme inhibitors. Many enzymes – such as protein kinases – adopt multiple conformations, and conformational interconversion is expected to impact on the design of small molecule inhibitors. We measured the dynamic equilibrium between DFG-in-like active and DFG-out-like inactive conformations of the activation loop of unphosphorylated Aurora-A alone, in the presence of the activator TPX2, and in the presence of kinase inhibitors. The unphosphorylated kinase had a shorter residence time of the activation loop in the active conformation and a shift in the position of equilibrium towards the inactive conformation compared with phosphorylated kinase for all conditions measured. Ligand binding was associated with a change in the position of conformational equilibrium which was specific to each ligand and independent of the kinase phosphorylation state. As a consequence of this, the ability of a ligand to discriminate between active and inactive activation loop conformations was also independent of phosphorylation. Importantly, we discovered that the presence of multiple enzyme conformations can lead to a plateau in the overall ligand Kd, despite increasing affinity for the chosen target conformation, and modelled the conformational discrimination necessary for a conformation-promoting ligand.

  • Journal article
    Storck Saha E, Morales Sanfrutos J, Serwa R, Panyain N, Lanyon-Hogg T, Tolmachova T, Ventimiglia L, Martin-Serrano J, Seabra M, Wojciak-Stothard B, Tate Eet al., 2019,

    Dual chemical probes enable quantitative system-wide analysis of protein prenylation and prenylation dynamics

    , Nature Chemistry, ISSN: 1755-4330

    Post-translational farnesylation or geranylgeranylation at a C-terminal cysteine residue regulates the localization and function of over 100 proteins, including the Ras isoforms, and is a therapeutic target in diseases including cancer and infection. Here, we report global and selective profiling of prenylated proteins in living cells enabled by the development of isoprenoid analogues YnF and YnGG in combination with quantitative chemical proteomics. Eighty prenylated proteins were identified in a single human cell line, 64 for the first time at endogenous abundance without metabolic perturbation. We further demonstrate that YnF and YnGG enable direct identification of post-translationally processed prenylated peptides, proteome-wide quantitative analysis of prenylation dynamics and alternative prenylation in response to four different prenyltransferase inhibitors, and quantification of defective Rab prenylation in a model of the retinal degenerative disease choroideremia.

  • Journal article
    Hansel C, Crowder S, Cooper S, Gopal S, Pardelha da Cruz J, De Oliveira Martins L, Keller D, Rothery S, Becce M, Cass A, Bakal C, Chiappini C, Stevens Met al., 2019,

    Nanoneedle-mediated stimulation of cell mechanotransduction machinery

    , ACS Nano, Vol: 13, Pages: 2913-2019, ISSN: 1936-0851

    Biomaterial substrates can be engineered to present topographical signals to cells which, through interactions between the material and active components of the cell membrane, regulate key cellular processes and guide cell fate decisions. However, targeting mechanoresponsive elements that reside within the intracellular domain is a concept that has only recently emerged. Here, we show that mesoporous silicon nanoneedle arrays interact simultaneously with the cell membrane, cytoskeleton, and nucleus of primary human cells, generating distinct responses at each of these cellular compartments. Specifically, nanoneedles inhibit focal adhesion maturation at the membrane, reduce tension in the cytoskeleton, and lead to remodeling of the nuclear envelope at sites of impingement. The combined changes in actin cytoskeleton assembly, expression and segregation of the nuclear lamina, and localization of Yes-associated protein (YAP) correlate differently from what is canonically observed upon stimulation at the cell membrane, revealing that biophysical cues directed to the intracellular space can generate heretofore unobserved mechanosensory responses. These findings highlight the ability of nanoneedles to study and direct the phenotype of large cell populations simultaneously, through biophysical interactions with multiple mechanoresponsive components.

  • Journal article
    Khan H, Seddon JM, Law RV, Brooks NJ, Robles E, Cabral JT, Ces Oet al., 2019,

    Effect of glycerol with sodium chloride on the Krafft point of sodium dodecyl sulfate using surface tension

    , JOURNAL OF COLLOID AND INTERFACE SCIENCE, Vol: 538, Pages: 75-82, ISSN: 0021-9797
  • Journal article
    Ces O, Elani Y, 2019,

    Community building in synthetic biology.

    , Exp Biol Med (Maywood), Vol: 244, Pages: 281-282
  • Conference paper
    Girvan P, Teng X, Brooks NJ, Baldwin GS, Ying Let al., 2019,

    Redox Kinetics of the Amyloid-Beta-Copper Complex and Its Biological Implications

    , 63rd Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 28A-28A, ISSN: 0006-3495
  • Journal article
    Rains JGD, ODonnelly K, Oliver T, Woscholski R, Long NJ, Barter LMCet al., 2019,

    Bicarbonate inhibition of carbonic anhydrase mimics hinders catalytic efficiency: Elucidating the mechanism and gaining insight toward improving speed and efficiency

    , ACS Catalysis, Vol: 9, Pages: 1353-1365, ISSN: 2155-5435

    Carbonic anhydrase (CA) mimics are often studied with a focus on the hydration of CO2 for atmospheric carbon capture. Consequently, the reverse reaction (dehydration of HCO3–) has received minimal attention, so much so that the rate-limiting step of the dehydration reaction in CA mimics is currently unknown. The rate-limiting step of the hydration reaction is reported to be the bicarbonate-bound intermediate step, and thus is susceptible to product inhibition. It is not, however, clear if this inhibition is a consequence of an increase in the rate of the competing dehydration reaction or resulting from the strong affinity of bicarbonate to the mimic. To address this, insight into the dehydration reaction kinetics is needed. We therefore report the most comprehensive study of a CA mimic to date. The dehydration profile of the fastest small-molecule CA mimic, ZnL1S, was characterized, and consequently evidence for the rate-limiting step for the dehydration reaction was seen to be the bicarbonate-bound intermediate step, much like the hydration reaction. This experimental validation of the rate-limiting step was achieved through a variety of methods including NMR experiments and the effect of inhibitors, substrate concentration, and metal center on activity. With this understanding, an improvement in the favorability of the rate-limiting step was achieved, resulting in decreased bicarbonate inhibition. Thus, an increase in the mimic’s kcat for both reactions was observed, resulting in the largest rate constants of any small-molecule CA mimic reported to date (28 093 and 579 M–1 s–1 for hydration and dehydration, respectively). Enzyme-like kcat/km values were obtained for ZnL1S (5.9 × 105 M–1 s–1 for CO2 hydration), and notably there is only a difference of 2.5 orders of magnitude from the enzyme, the closest of any CA mimic reported in the literature. The results from this work can be applied to the development and improvement

  • Journal article
    Cecchetti C, Pyle E, Byrne B, 2019,

    Transporter oligomerisation: roles in structure and function

    , Biochemical Society Transactions, Vol: 47, Pages: 433-440, ISSN: 0300-5127

    Oligomerisation is a key feature of integral membrane transporters with roles in structure, function and stability. In this review, we cover some very recent advances in our understanding of how oligomerisation affects these key transporter features, with emphasis on a few groups of transporters, including the nucleobase ascorbate transporters, neurotransmitter sodium symporters and major facilitator superfamily members.

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

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